JP2009528289A - Methods of modulating neurotransmitter systems by inducing counter adaptation - Google Patents

Abstract

The present invention relates to methods of modulating neurotransmitter systems by inducing counteradaptive responses. According to one embodiment of the invention, the method of modulating a neurotransmitter comprises a ligand for a receptor in a neurotransmitter system such that the ratio of the administration half-life to the period between administrations is ½ or less. Is repeatedly administered. The methods of the present invention can be used to address a number of undesirable mental, neurological and physiological conditions.

Description

  This application is a continuation-in-part of U.S. Patent Application No. 11 / 234,850 filed on September 23, 2005 under 35 U.S.C. ), Filed on September 23, 2004, entitled “COUNTER-ADAPTATION THERAPY FOR TREATMENT OF DEPRESSION AND OTHER MENTAL CONDITIONS” Claims the benefit of provisional patent application number 60 / 612,155. This application is a US application filed on February 27, 2006 entitled "METHOD OF REGULATING THE CRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS". Provisional Patent Application No. 60 / 777,190 and US Provisional Patent Application No. filed November 9, 2006 entitled “OPIATE ANATOGONISTS FOR COUNTERADAPTATION THERAPY” Claim priority to 60 / 858,186. The provisional application referred to above is incorporated herein by reference in its entirety.

  The present invention relates to neurotransmitter systems. The invention particularly relates to a method of modulating these neurotransmitter systems by inducing counteradaptative responses.

  Mood, mood disorders, and related conditions are the result of complex intertwined central nervous system events that correlate multiple neurotransmitter systems. The most common mood disorder is depression. Depression is a clinical diagnosis with numerous physical and mental symptoms due to modulation of multiple neurotransmitter systems. The neurotransmitter systems most commonly associated with depression are the norepinephrine and serotonin systems, but in the current study the substance P system, the dynorphin system (kappa receptor), the endogenous endorphin system (mu and delta opiates) Other systems such as the receptor), the corticotropin releasing factor system, and the arginine vasopressin system have also been shown to be involved in depression. In addition, these neurotransmitter systems are bipolar, obsessive-compulsive, anxiety, phobias, stress disorders, drug abuse, sexual disorders, eating disorders, motivational disorders, pain disorders, cardiovascular It also pertains to many other undesirable mental, neurological and physiological conditions, including disorders, age related disorders, and immune related disorders.

Conventional strategies for treating conditions related to neurotransmitters center around the improvement of abnormally high or low levels of synaptic neurotransmitters. Conventional therapeutic agents act directly to regulate the function of the neurotransmitter system. Such agents are anxiolytics, hypnotics or selective reuptake inhibitors, such as benzodiazepines (eg, diazepam, lorazepam, alprazolam, temazepam, flurazepam, and chlodiazepoxide), TCA, MAOI, SSRI (eg, Fluoxetine hydrochloride), NRI, SNRI, CRF modulating agent, serotonin presynaptic autoreceptor antagonist, 5HT ₁ agonist, GABA-A modifying agent, serotonin 5H _2c and / or 5H _2B modifying agent, beta-3 Adrenergic receptor agonists, NMDA antagonists, V1B antagonists, GPCR modifiers, dynorphin antagonists, and substance P antagonists.

  Conventional therapeutics and methods are effective to some extent but have several disadvantages. For example, the use of many conventional therapeutic agents is associated with side effects such as sexual dysfunction, nausea, irritability, fatigue, dry mouth, visual impairment and weight gain. In addition, patients may become accustomed to, or become tolerant to, conventional treatments with repeated use, and the efficacy of those treatments is lost over time.

  One aspect of the present invention relates to a method of modulating a neurotransmitter system containing one type of receptor by inducing counter-adaptation in a patient. The method comprises the step of repeatedly administering to the patient a ligand for the one type of receptor, each dose having a dose half-life, wherein the ligand is made to that type of receptor in a first period associated with each dose. Binding, thereby inducing, maintaining or improving counter adaptation. The counter-adaptation causes modulation of the neurotransmitter system. The ratio of the half-life for administration to the period between doses is ½ or less.

  In one aspect of the present invention, the neurotransmitter system is an SP system, the one type of receptor is an SP receptor, the ligand is an SP receptor agonist, and the counteradaptation causes down-regulation of the SP system. cause.

  In another aspect of the invention, the neurotransmitter system is the endogenous endorphin system, the one type of receptor is a mu opiate receptor and / or a delta opiate receptor, and the ligand is mu and / or opiate receptor. It is a body agonist and the counterindication causes an upregulation of the endogenous endorphin system.

  In still another aspect of the present invention, the neurotransmitter system is a dynorphin system, the one kind of receptor is a kappa receptor, the ligand is a kappa receptor agonist, and the counteradaptation is a dynorphin system. Cause down regulation.

  In yet another aspect of the invention, the neurotransmitter system is a serotonin system and the counter-adaptation causes an upregulation of the serotonin system. Thus, in one embodiment of this aspect of the invention, the type of receptor is a serotonin presynaptic autoreceptor and the ligand is a serotonin presynaptic autoreceptor agonist. In another embodiment of this aspect of the invention, the one type of receptor is a serotonin post-synaptic receptor and the ligand is a serotonin post-synaptic autoreceptor antagonist.

  In yet another aspect of the invention, the neurotransmitter system is the norepinephrine system and the counteradaptation causes an upregulation of the norepinephrine system. Thus, in one embodiment of this aspect of the invention, the type of receptor is a norepinephrine presynaptic alpha-2 adrenergic receptor and the ligand is a norepinephrine presynaptic alpha-2 adrenergic receptor agonist. . In another embodiment of this aspect of the invention, the type of receptor is a norepinephrine post-synaptic adrenergic receptor and the ligand is a norepinephrine post-synaptic adrenergic receptor antagonist.

  In yet another aspect of the present invention, the neurotransmitter system is a CRF system, the one type of receptor is a CRF receptor, the ligand is a CRF receptor agonist, and the counteradaptation is down-regulation of the CRF system. Causes regulation.

  In yet another aspect of the invention, the neurotransmitter system is a CRF system, the one type of receptor is a CRF receptor, the ligand is a CRF receptor antagonist, and the counter-adaptation is up-regulation of the CRF system. Causes regulation.

  In yet another aspect of the invention, the neurotransmitter system is an AVP system, the one type of receptor is an AVP receptor, the ligand is an AVP receptor agonist, and the counteradaptation is a down-regulation of the AVP system. Causes regulation.

  In yet another aspect of the invention, the neurotransmitter system is an AVP system, the one type of receptor is an AVP receptor, the ligand is an AVP receptor antagonist, and the counteradaptation is an up-regulation of the AVP system. Causes regulation.

  In yet another embodiment of the invention, a method is provided for inducing modulation of a neurotransmitter system comprising one type of receptor associated with an undesired mental, neurological or physiological condition. The method comprises the step of repeatedly administering to the patient a ligand for said type of receptor, each dose having a dose half-life, wherein said ligand is associated with that type of receptor in a first period associated with each dose. Binding to a substantial number of them, thereby inducing counter adaptation. The counter-adaptation causes modulation of the neurotransmitter system in a second period associated with each administration, the second period following the first period.

  In yet another aspect of the invention, the method described herein is for treating or treating an undesirable mental, neurological or physiological condition in a patient associated with a receptor of the receptor type. Used.

  In yet another aspect of the invention, the methods described herein are used to treat or treat a condition associated with an undesirable immune system of a patient in need thereof, wherein the condition associated with the immune system is the aforementioned In connection with receptors of the receptor type, the method causes upregulation of the immune system.

  In yet another aspect of the invention, the methods described herein are used to treat or treat a condition associated with cardiovascular or lipid or cholesterol metabolism in a patient in need thereof, said cardiovascular or lipid or Conditions associated with cholesterol metabolism are associated with receptors of the receptor type.

In yet another aspect of the invention, the methods described herein are used to treat or treat a lack of preparation for future athletic activities.
In yet another aspect of the invention, the methods described herein are used to treat or treat undesirable conditions associated with the Sirt1 pathway.

  The method of the present invention provides many advantages over prior art methods. For example, the methods of the present invention can be used to address many undesirable mental, neurological and physiological conditions with fewer side effects. In certain embodiments of the invention, the desired therapeutic utility can be set to coincide with the desired time of day or the work performed by the patient.

  Additional features and advantages of the invention will be set forth in the detailed description that follows, and in part will be readily apparent to those skilled in the art from the description, or may be found in the specification and claims, and the drawings described in the accompanying drawings. It will be appreciated by practicing the invention.

  Both the foregoing summary and the following detailed description are exemplary of the invention and are intended to provide an overview or configuration in order to understand the nature and characteristics of the claimed invention. Yes.

  The accompanying drawings are included to provide a further understanding of the invention, and are incorporated in and constitute a part of this specification. The drawings are not necessarily to scale, and the sizes of the elements may have been changed for clarity. The drawings illustrate one or more embodiments of the invention and, together with the description, serve to explain the principles and operations of the invention.

  The present invention relates to the modulation of neurotransmitter systems by utilizing the patient's response to drugs (“counter adaptation”) rather than relying on the direct effects of the drug to improve the clinical efficacy of the patient. In general, the drug is selected so that the counter-indication is beneficial to the patient and ultimately can provide the desired long-term effect. The method of the present invention differs from conventional methods in that the direct effect of the drug is modulation of neurotransmitter receptors that are generally associated with worsening symptoms. However, in response to the direct effects of the drug, the brain responds with a counter-adaptation that results in the desired modulation of the neurotransmitter system when any direct effect of the drug decreases. The modulation can be any change in the function of the neurotransmitter system, for example up-regulation or down-regulation. A specific acute response is directly triggered to indirectly produce the desired long-term effect. As a simple illustration, euphoria-stimulating agents, such as morphine and cocaine, cause depression in withdrawal symptoms and dysphoria-stimulating agents in withdrawal symptoms Brings antidepressant.

  One embodiment of the invention relates to a method of modulating a neurotransmitter system. In general, the neurotransmitter system is a system of natural neurotransmitter compounds and synaptic receptors involved in signal transmission of the central nervous system. The neurotransmitter system includes a type of receptor. Said kind of receptors may be associated, for example, with undesirable mental, neurological or physiological conditions. FIG. 1 includes a graph of ligand concentration versus time in vivo in a method according to one embodiment of the invention. As shown in FIG. 1, the method comprises the step of repeatedly administering to a patient a ligand for said type of receptor, thereby binding that type of receptor to the ligand in a first period associated with each administration. . As used herein, a ligand is a compound that binds to a receptor of the receptor type (eg, interacts covalently or non-covalently) and the ligand is, for example, a receptor It may be an agonist or an antagonist of the receptor. Counter-adaptation is triggered by binding of the ligand to the receptor, and counter-adaptation causes modulation of the neurotransmitter system. FIG. 1 shows several doses of ligand in the middle of the method, not the first few doses. Each administration is a single cycle in which the in vivo concentration of the ligand starts at the baseline level, reaches a maximum level, and falls back to the baseline level. The graph in FIG. 1 shows two such administrations. Each administration of the ligand depends on the dosing regimen, for example, to the patient as a single unit (eg, tablet, capsule) or injection, multiple units or injection, or continuous (eg, intravenous or sustained release). Sex patch).

Examples of neurotransmitter system types and receptor types in which the method can be implemented include substance P systems in which one type of receptor can be an NK-1, NK-2 and / or NK-3 receptor; Endogenous endorphins that can be mu and / or delta opiate receptors; dynorphins that can be a kappa receptor; receptors that are inhibitory serotonin presynaptic autoreceptors (eg, 5HT _1A and / or 5HT _1B autoreceptors) and / or serotonin post-synaptic receptors (eg, 5HT ₁ , 5HT ₂ , 5HT ₃ , 5HT ₄ , 5HT ₅ , 5HT ₆ and / or 5HT ₇ receptors) Serotonin system to obtain; one type of receptor is inhibitory norepinephrine presynaptic alpha-2 adrenergic receptor And / or norepinephrine system, which may be a post-synaptic adrenoceptor of norepinephrine; and a corticotropin releasing factor (CRF) in which one type of receptor may be a CRF receptor (eg, CRF-1 receptor and / or CRF-2 receptor) And the arginine vasopressin (AVP) system in which the type of receptor can be an AVP receptor (eg, V1R, also known as V1a, V2R, and / or V3b). As those skilled in the art will appreciate, these neurotransmitter systems and receptor types are associated with a variety of undesirable mental, neurological and physiological conditions.

  In certain embodiments of the invention, the undesired mental, neurological or physiological condition is associated with a type of receptor in the neurotransmitter system. When a receptor binds to its natural neurotransmitter and an undesirable mental, neurological or physiological condition is exacerbated, it is said to be “positively associated” with that type of receptor. Conversely, if a receptor binds to its natural neurotransmitter and an undesired mental, neurological or physiological condition is improved, it is said to be “negatively related” to that type of receptor. . For example, serotonin post-synaptic receptors alleviate depression by binding to their natural neurotransmitter serotonin, so the undesirable mental, neurological or physiological state of depression is Negatively associated with the receptor. Since kappa receptors exacerbate depression by binding to their natural neurotransmitter dynorphin, undesirable mental, neurological or physiological states of depression are positive for kappa receptors. Related.

  The method of the present invention utilizes an indirect counteradaptive action to augment or suppress the neurotransmitter system, instead of relying on the direct effects of ligand receptors that bind to modulate the neurotransmitter system. . Counter-adaptation is the natural response of the brain to ligand binding. As an initial effect of ligand binding, undesirable mental, neurological or physiological conditions associated with the neurotransmitter system may be exacerbated. However, counter-adaptation results in an overall desirable modulation of the neurotransmitter system since the effect of the counter-adaptation persists over time and can be increased through repeated administration of the ligand after the ligand is removed from the system. And modulation of the neurotransmitter system can provide a therapeutic effect with respect to undesirable mental, neurological or physiological conditions. The modulation of the neurotransmitter system may be, for example, an increase in the counteradaptive response (as shown in FIG. 2 described below) or already (as shown in FIG. 6 described below). It may be the maintenance of the counteradaptive response being induced.

  Counter-adaptation is a way in which the central nervous system maintains homeostasis. Counter-adaptation is the result of an attempt by the body to adjust the neurotransmitter system to its original steady level in order to prevent its overstimulation or understimulation. Natural neurotransmitters bind to their receptors for only a short period of time and are almost immediately removed from the synapse, thus causing no counteradaptive response. However, it acts to counteract the direct effects of ligand-receptor binding when the ligand interacts with the receptor for longer periods of time (eg, because the ligand has a longer binding time or is administered continuously). Cellular mechanisms that occur gradually occur at the receptor / neurotransmitter level (ie, counteradaptation). Counter-adaptations include, for example, changes in biosynthesis or release of natural neurotransmitters that bind to the one type of receptor, changes in reuptake of natural neurotransmitters that bind to the one type of receptor, A change in the number and / or the number of binding sites on the receptor of the type of receptor, a change in the sensitivity of the receptor of the type of receptor to binding by natural neurotransmitters and / or receptor agonists, or It can be a combination. Ligand use thus induces (ie, causes) counter adaptation by stimulating processes that counteract the initial effects of the ligand. Such counter adaptation reduces the effects of ligand-receptor binding over time.

  When the ligand is a receptor agonist, the counteradaptation acts to reduce the functionality of the neurotransmitter system (ie “down-regulation”). Down-regulation can be, for example, decreased biosynthesis or release of natural neurotransmitters that bind to the one type of receptor, increased reuptake of natural neurotransmitters that bind to the one type of receptor, A decrease in the number and / or the number of binding sites on the receptor of the type of receptor, a decrease in the sensitivity of the receptor of the type of receptor to binding by natural neurotransmitters and / or receptor agonists, or Can occur by combination. Any of the counteradaptive responses listed above act to reduce the function of the neurotransmitter system, and thus with respect to undesirable mental, neurological or physiological conditions positively associated with the neurotransmitter system A therapeutic effect can be provided.

  Conversely, when the ligand is a receptor antagonist, counter-adaptation acts to enhance the functionality of the neurotransmitter system (ie, “up-regulation”). Up-regulation can be, for example, increased biosynthesis or release of natural neurotransmitters that bind to the one type of receptor, decreased reuptake of natural neurotransmitters that bind to the one type of receptor, Increasing the number of and / or the number of binding sites on the receptor of said kind of receptor, increasing the sensitivity of said kind of receptor to binding by natural neurotransmitters and / or receptor agonists, or Can be produced by a combination of Any of the counter-adaptive responses listed above act to enhance the functionality of the neurotransmitter system, and thus an undesirable mental, neurological or physiological condition that is negatively associated with the neurotransmitter system Provide a therapeutic effect.

  Receptors in the brain are generally regulated by a pre-synaptic negative inhibition control loop. Therefore, for post-synaptic receptors that elevate mood (ie, receptors that are negatively associated with undesirable mental, neurological, or physiological conditions), use repetitive agonist therapy at the relevant inhibitory presynaptic receptor It is desirable. Repeated administration of an agonist at a presynaptic inhibitory receptor results in downregulation of that receptor, increasing its neural firing at a post-synaptic receptor that elevates mood by reducing its inhibitory response, Improve mood.

  The opposite strategy is desirable for use with post-synaptic receptors that cause mood depression (ie, receptors positively associated with undesirable mental, neurological or physiological conditions). For such receptors, it is desirable to use repetitive antagonist therapy at the relevant inhibitory presynaptic receptor. Repeated administration of an antagonist at a presynaptic inhibitory receptor results in upregulation of that receptor and reduces its inhibitory response, thereby reducing neural excitement at the post-synaptic receptor that causes mood depression and improving mood .

  The direct effect of the ligand that binds in the first period is often an early exacerbation of an undesirable mental, neurological or physiological condition associated with a type of receptor. For example, if the administered ligand is an antagonist to a type of receptor that is negatively associated with an undesired mental, neurological or physiological condition, the short-term effects of binding block the receptor and It is to prevent the receptor from binding to the natural neurotransmitter and firing. Similarly, if the administered ligand is an agonist for a type of receptor positively associated with an undesired mental, neurological or physiological condition, the short-term effect of binding is to excite the receptor. It is. Receptor excitement positively associated with an undesired mental state, neurological or physiological state, and receptor excitement negatively associated with an undesired mental, neurological or physiological state Both can cause worsening of early symptoms. As the short-term effects of ligand receptor binding diminish (eg, by removal of the ligand from the system), counteradaptation continues to provide the desired modulation of the neurotransmitter system. Repeated administration can gradually increase the regulation of the neurotransmitter system. In certain embodiments of the invention described below, measures are taken to limit the impact on the patient of the direct effects of ligand-receptor binding.

  FIG. 1 includes, in part (b), a graph of mood versus time for administration of the appropriate ligand to a mood-related receptor. As shown in the example of FIG. 1, the direct effect of ligand administration can be a worsening of mood in each first period. This exacerbation of mood diminishes as the in vivo concentration of the ligand decreases to its steady state level. After the ligand concentration has returned to its low steady state level, the counteradaptation remains intact in the second period following the first period associated with each administration, resulting in an overall improvement in mood. FIG. 2 is a graph of mood versus time for several doses of ligand during the method according to the invention. The strength of the counteradaptation, as evidenced by the upward trend in FIG. 2 (ie, the graph generally slopes upward with respect to time), is due to each administration causing an additional counteradaptive response. , Increase with time. Therefore, an increase in therapeutic effect can be realized by repeated intermittent administration of the ligand. 1 and 2 show examples where counter-adaptation causes an increase in mood, but the method described here treats any condition involving neurotransmitters, including those described in more detail below. Those skilled in the art will recognize that it is useful to do so.

  Each dose of ligand has a dose half-life. As shown in the graph of part (a) of FIG. 1, the in vivo concentration of the ligand is relatively high at the start of administration (eg, swallowing a tablet, applying a transdermal patch, or starting intravenous administration). It is at a low baseline level and then rises to some maximum level. After reaching a maximum value, the in vivo concentration of the ligand decreases (eg, due to ligand metabolism / excretion) and returns to baseline levels and remains at baseline levels until the next dose. As shown in FIG. 1, the dosing half-life is measured as the period between the start of dosing and the point at which the in vivo concentration is half of the maximum as the concentration drops from its maximum level to baseline .

  The administration half-life will be a function of the compound half-life (ie, the in vivo half-life of the ligand compound itself) as well as the route of administration. For example, FIG. 3 is a graph of in vivo concentration versus time for a single dose by injection of a ligand with a relatively long compound half-life. Injections allow ligands to enter the bloodstream so quickly that the half-life of administration approximates the compound half-life. In the example of FIG. 4, a ligand with a much shorter compound half-life is administered using a time-release transdermal patch. Here, the concentration rises more slowly to the steady state maximum concentration and then decreases as the patch is depleted. If the patch is removed before it is depleted, the in vivo concentration will drop rapidly to the baseline level, as shown in FIG. The half-life of administration may be, for example, less than about one week, less than about 3 days, or less than about 1 day. More desirably, the administration half-life can be less than about 16 hours, less than about 12 hours, less than about 8 hours, or less than about 4 hours. In certain embodiments of the invention, particularly those using ligands with relatively long compound half-lives, the administration half-life may be greater than about 4 hours, greater than about 12 hours, It may be longer than about 16 hours, or may be longer than about 30 hours.

  The ligand has a compound half-life defined as the in vivo half-life of the ligand and its active metabolite (ie, a metabolite active at the receptor type of receptor), which compound half-life is determined by the route of administration. It has nothing to do with any effects of. In certain embodiments of the invention, it may be desirable to use a compound that has a relatively short compound half-life. For example, in certain embodiments of the invention, the compound half-life is less than about 1 week, less than about 3 days, or less than about 1 day. More desirably, the compound half-life can be less than about 16 hours, less than about 12 hours, less than about 8 hours, less than about 4 hours, or less than 1 hour. However, some ligands have a relatively longer compound half-life. For example, in certain embodiments of the invention, the compound half-life of the ligand may be greater than about 4 hours, greater than about 12 hours, greater than about 16 hours, It may be longer than about 30 hours.

  The time period between doses is desirably selected so that the direct effect of ligand-receptor binding is acceptable and remains acceptable and maximizes the counter-adaptive response to the ligand. For example, administration of the ligand may be performed daily. In other embodiments of the invention, the period between administrations may be 2 days or more, 3 days or more, 5 days or more, 1 week or more, 2 weeks or more, or 1 month or more. Similarly, the dose of ligand for each dose is selected to be sufficient to cause a counter-adaptive response, but low enough that the direct effect of ligand-receptor binding is low and can be tolerated by the patient.

  When using a ligand with a compound half-life longer than about 12 hours, it may be desirable to repeatedly administer a second ligand to said type of receptor in order to increase counter-adaptation. Each dose of the second ligand has a dose half-life of less than about 8 hours. In an example of a method according to the invention, a ligand having a compound half-life of 24 hours is administered every 3 days with a dosing half-life of 24 hours and a second ligand is administered daily with a dosing half-life of 6 hours. In such cases, when the ligand is a receptor agonist, the second ligand is desirably a receptor agonist, and when the ligand is a receptor antagonist, the second ligand is desirably a receptor antagonist.

  The ratio of dose half-life to period between doses is desirably selected to maximize counter-adaptation while maintaining any direct effect of ligand binding in the first period at a low acceptable level. . According to one embodiment of the invention, the ratio of the administration half-life to the period between administrations is ½ or less. Desirably, the ratio of the administration half-life to the period between administrations is 1/3 or less. In certain embodiments of the invention, the ratio of the administration half-life to the period between administrations is 1/5 or less, 1/8 or less, or 1/12 or less. However, it may be desirable to administer the ligand relatively frequently to maintain the desired level of counter-adaptation. For example, in certain desirable embodiments of the invention, the ratio of dosing half-life to dosing interval is greater than 1/100, greater than 1/50, greater than 1/24, greater than 1/12. , Greater than 1/8, greater than 1/5, greater than 1/4, or greater than 1/3.

  A substantial number of the types of receptors are desirably bound to the ligand in the first time period associated with each administration so as to provide a counteradaptation for ligand binding. For example, at least about 30%, at least about 50%, at least about 75%, or at least about 90% of the receptors of the receptor type are desirably bound by the ligand in each first period.

  Similarly, the first period associated with each administration is desirably long enough to cause substantial counter-adaptation. For example, the duration of each first period is desirably at least about 5 minutes, at least about 30 minutes, at least about 1 hour, at least about 2 hours, or at least about 4 hours. In certain preferred embodiments of the present invention, the duration of the first period is about 8 hours. However, if the direct effect of ligand binding is a significant worsening of an undesirable condition, it may be desirable to maintain the first period below the period necessary to obtain an acceptable level of counter-adaptation. For example, in certain embodiments of the present invention, the duration of the first period is desirably less than about 24 hours, less than about 16 hours, less than about 12 hours, less than about 8 hours, or less than about 6 hours.

  In a preferred embodiment of the invention, a significant number of receptors remain unbound to the ligand in the second period following each first period associated with each administration. Low levels of ligand-receptor binding allow the patient to enjoy a counter-adapted effect (eg, a therapeutic effect) without being hindered by any deleterious effects of direct ligand binding. For example, during each second period, desirably no more than about 50%, no more than about 25%, no more than about 10% of the receptor is bound to the ligand.

  During the second period associated with each administration, a significant number of the one type of receptors are not bound to the ligand. In each second period, no direct ligand-receptor binding effect remains, so the patient can enjoy any therapeutic effect of the counter-adaptation. Therefore, it is desirable that each second period is as long as possible. For example, the duration of each second period is desirably at least about 2 hours, at least about 10 hours, or at least about 15 hours. However, it may be desirable to keep each second period relatively short in order to increase counter-adaptation by shortening the period between doses. For example, in certain embodiments of the present invention, the duration of each second period is desirably about 20 hours or less, about 30 hours or less, about 50 hours or less.

  To increase counter-adaptation over time and minimize any initial undesirable mental, neurological or physiological deterioration, treat with a relatively low dose of ligand at each dose It may be desirable to start and increase the dosage over time. Dose escalation can also be used to compensate for increased tolerance of the patient to the ligand. For convenience, it may be desirable to increase the dose intermittently over time (ie, increase the dose over a longer period than between administrations). For example, in an embodiment of the present invention, the dosage is from 1 week to 2 weeks or more, 3 weeks or more, 1 month or more, 2 months or more, 3 months or more, 6 months or more from increasing to increasing Or, it is increased after a period of one year or more. For each dose increase, the dose is desirably increased by at least about 5%, at least about 10%, at least about 25%, at least about 50%, or at least about 100% of the initial amount. However, it may be desirable to maintain a maximum dosage within a certain range. For example, in certain embodiments of the invention, the maximum dose may be within 300 times the initial dose, within 100 times the initial dose, within 50 times the initial dose, or within 20 times the initial dose. .

  In one example of a dosing schedule, a low amount of ligand is given for 1 week, 2 weeks, or 3 weeks. These initial amounts are high enough to elicit a counteradaptive response, but low enough to produce only a direct effect with minimal ligand-receptor binding. Thereafter, the dosage is increased. The increase may be on the order of 10%, but it is desirable to at least double the initial amount in order to induce a counteradaptive response more quickly. The dose is increased again after 4-6 weeks. Follow this pattern every 1 month, 2 months, 4 months, or 6 months. The end point of the maximum dose will depend on the individual tolerance to the ligand and the onset of side effects and direct effects with higher doses.

  In order to reduce the impact of any direct effects of ligand-receptor binding, it may also be desirable to time the administration of the ligand such that the first period occurs during a time when adverse effects on the patient are minimized. is there. When a patient is asleep, the patient will not notice many of the direct effects of ligand-receptor binding (eg, decreased mood). For example, it may be desirable to time the administration of the ligand such that a substantial portion of the first period occurs during patient sleep. As a result, any direct effects of ligand-receptor binding are not noticed. For example, desirably at least 40%, at least 60%, or at least 85% of the first period occurs during the patient's sleep. In order to achieve such timing, it may be desirable to perform a substantial portion of the administration of the ligand within a certain time before the patient goes to bed. For example, desirably at least 50%, at least 75%, at least 90%, or at least 95% of the ligand administration occurs within a certain time before the patient goes to bed.

  However, daytime administration is not contraindicated, and in other embodiments of the invention, each administration of the ligand is performed 1 hour before the patient goes to bed. In an example of the method according to the invention, patients who received the ligand daily for 2 or 3 months developed a counter-adaptation, for example showing some associated mood improvement. If there is a specific time that the patient wants to improve daytime mood, the time of ligand administration can be shifted so that the desired time falls within the second period associated with that administration. If the patient desires an exhilarating mood at 6 pm, the patient can be administered an appropriate ligand (eg, a naloxone, mu and / or delta opiate receptor antagonist with a compound half-life of 1 hour) at 2 pm. The direct effect of naloxone receptor-binding (unpleasant mood) lasts only a few hours, leaving only the good mood brought about by counter-adaptation until 6 pm.

  The administration of the ligand is desirably repeated as many times as necessary to establish a reasonably large counteradaptation effect. Thus, in the methods of the present invention, desirably the administration is performed at least 5, at least 10, at least 25, or at least 50 times.

  Each ligand is administered by oral, transdermal, inhalation, subcutaneous, intravenous, intramuscular, intrathecal, intrathecal, transmucosal, or osmotic pressure This can be done by using a pump, microcapsule, implant or suspension. One of skill in the art will select the route of administration based on the uniqueness of the ligand, its compound half-life, the desired dosage, and the desired half-life of administration.

  Rapidly absorbed loading dose (to obtain fast ligand-receptor binding) and slowly absorbed dose (to maintain the desired level of ligand receptor binding over a first period of the desired length) )) And it may be desirable to administer the ligand. For such administration, rectal suppositories having a rapidly absorbing outer layer and a slower absorbing core may be used. Alternatively, a loading dose can be applied sublingually and a slowly absorbed dose can be applied transdermally via a patch.

  A carrier in the blood can be used to increase the dosing half-life of the ligand if it is circulating. For example, US Pat. Nos. 6,610,825 and 6,602,981, each of which is hereby incorporated by reference in its entirety, describe that ligands can be added to blood cells or proteins to increase the dosing half-life of the ligand. Describes how they are combined. Adessi et al. (Curr Med Chem, 9 (9); May 2002; 963-978) describe a method for stabilizing peptide ligands.

  The methods of the invention can be used to treat or treat any undesirable condition associated with a neurotransmitter system. Examples of such conditions include chronic pain, mood disorders, eating disorders, anxiety disorders, motivation and ability problems, inflammatory conditions, nausea, vomiting, urinary incontinence, rash, erythema, rash, cardiovascular conditions, Immune system related conditions, and effects of aging. More examples of undesirable mental, neurological or physiological conditions are described below.

  In order to reduce any direct effect of ligand-receptor binding, it may be desirable to administer an anxiolytic in combination with the ligand. Anti-anxiety drugs can help alleviate the effects of ligand-receptor binding, particularly on patient sleep. An anxiolytic agent may, for example, affect the GABA pathway. The anxiolytic agent can be, for example, benzodiazepines such as diazepam, lorazepam, alprazolam, temazepam, flurazepam, and chlordiazepoxide. Similarly, in order to reduce any direct effects of ligand-receptor binding, it may be desirable to administer a hypnotic or selective serotonin reuptake inhibitor in combination with the ligand. Each of these agents may be administered at the same time as the ligand or may be administered at different times. It may also be desirable to add tryptophan to the patient's diet, as described in US Pat. Nos. 4,377,595 and 5,958,429. Each of these patent documents is incorporated herein by reference in its entirety.

  In some examples, one direct effect of ligand-receptor binding is a decrease in immune system function. Thus, it may be desirable to administer the autoimmune drug in the first period in combination with the ligand. Examples of suitable autoimmune therapies include medications such as corticosteroids, chlorambucil, cyclosporine, cyclophosphamide, methotrexatate, azathioprine, TNFα antagonists, and therapies such as systemic enzyme therapy, gene therapy and radiation therapy Is mentioned. Of course, as will be appreciated by those skilled in the art, other autoimmune drugs, including those developed in the future, can also be used in the methods of the invention. In certain embodiments of the invention, autoimmune therapy is not performed during the second period.

  Similarly, it may be desirable to administer an antiviral agent in the first period in combination with a ligand. Examples of suitable antiviral agents include interferon, ribavirin, protease inhibitors, amantadine, rimantadine, pleconaril, antibodies (monoclonal, anti-VAP, receptor anti-idiotype, foreign receptor, and synthetic receptor mimics), acyclovir , Zidovudine (AZT), lamivudine, RNAase H inhibitors, integrase inhibitors, inhibitors of transcription factor adsorption to viral DNA, so-called “antisense” molecules, synthetic ribozymes, zanamivir, and osretamivir. Of course, as will be appreciated by those skilled in the art, other antiviral agents, including those developed in the future, can be used in the methods of the present invention. In certain embodiments of the invention, the antiviral agent is not administered during the second period.

  Similarly, it may be desirable to administer antibacterial, antifungal, and / or anti-neoplastic agents in the first period in combination with a ligand. In certain embodiments of the invention, the antibacterial agent, antifungal agent, and / or antifungal agent is not administered during the second period.

  It may be desirable to administer the anticancer agent in the first period in combination with the ligand. Suitable anti-cancer agents include, for example, adriamycin, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide, mechloretamine, melphalan, procarbazine, temozolamide, daunorubicin, doxorubicin, idarubicin, bleomycin, mitomycin, mitomycin tacitramine, pricamycin, , Fluorouracil, hydroxyurea, methotrexate, asparaginase, pegase pargase, irinotecan, topotecan, bicalutamide, estramustine, flutamide, leuprolide, megestrol, nilutamide, testosterone, triptorelin, anastrazol, letrozole, aldesleukin, alemtuzumab, Gemtuzumab, toremifene, trastuzumab, Toposide, docetaxel, paclitaxel, vinblastine, vincristine, vinorelbine, altretamine, erlotinib, greebeck, curcumin, tamoxifen, bortezomib, gefitinib, imatinib, 3,4-methylenedioxy-5,4'-dimethoxy-3'-amino-Z -Stilbene derived cancer cell growth inhibitor, hydroxyphenstatin and its sodium diphosphate prodrug, histone deacetylase inhibitor, suberoylanilide hydroxamic acid, trichostatin A, sodium butyrate, metformin, 5-lipoxygenase (5- LO) antagonists, antisense oligonucleotides targeting the RIα regulatory subunit of protein kinase A type I, vitamin E and its analogs, vitamin E succina (VES), as well as gene therapy. Of course, as will be appreciated by those skilled in the art, other autoimmune drugs, including those developed in the future, can be used in the methods of the present invention. In certain embodiments of the invention, the antiviral agent is not administered during the second period.

It may be desirable to administer a conventional pharmaceutical agent (eg, simultaneously or sequentially) in combination with a ligand. Such an agent is an agonist for a kind of receptor whose number and / or sensitivity has been increased by counter-adaptation, or for a kind of receptor whose number and / or sensitivity has been decreased by counter-adaptation It is particularly desirable when it is an antagonist. Examples of conventional pharmaceuticals administered in combination with ligands include TCA, MAOI, SSRI, NRI, SNRI, CRF modifier, serotonin presynaptic autoreceptor antagonist, 5HT ₁ agonist, dynorphin antagonist, GABA-A modifier , Serotonin 5H _2c and / or 5H _2B modulators, beta-3 adrenergic receptor agonists, NMDA antagonists, V1B antagonists, GPCR modulators, or substance P antagonists. Desirably, the additional pharmaceutical agent has a relatively short dosing half-life so that the pharmaceutical agent can be administered during the second period such that its effect is nearly abolished by the next administration of the ligand. Such a regimen maintains a high level of counter-indication while maximizing the effect of the drug during the second period.

  In order to provide the desired clinical effect, it may be desirable to take advantage of the direct binding of the receptor. For example, if the ligand is a receptor agonist, it may be desirable to administer an antagonist to one type of receptor during one or more of the second periods following the first period associated with each administration. However, antagonists for one type of receptor are desirably not administered during the first period associated with each administration. Similarly, if the ligand is a receptor antagonist, it may be desirable to administer an agonist for one type of receptor in one or more of the second periods following the first period associated with each administration. However, agonists for one type of receptor are desirably not administered during the first period associated with each administration. Preferably, the antagonist has an in vivo half-life of less than 12 hours, less than 8 hours, or less than 6 hours so that the antagonist does not affect subsequent administration of the agonist.

  Another embodiment of the invention is illustrated by the in vivo ligand concentration (part a) and mood versus time (part b) graphs of FIG. In this method, a counter-adaptation is first induced by giving the patient one or more doses of a ligand for a type of receptor. As shown in FIG. 6, this can be done by repeatedly or continuously administering high doses of ligand. Relatively high and long-term administration of the ligand will induce a strong counter-adaptive effect, but tolerate the patient with a significant direct effect of ligand-receptor binding as shown in the mood versus time graph of FIG. Sometimes. In such cases, it may be desirable to keep the patient hospitalized during the induction of the counteradaptive response in the early stages. After a counter-adaptive response is elicited, the counter-adaptive response is maintained with repeated doses of ligand to the patient, with a ratio of dose half-life to period between doses of ½ or less. Repeated administration can be performed approximately as described above.

  Even though the method of the present invention is unable to heal undesirable mental, neurological and physiological conditions, the method of the present invention can be used to modulate the function of the neurotransmitter system, thereby reducing undesired mentality. , Neurological and physiological conditions can be improved. The methods of the present invention may make undesirable mental, neurological and physiological conditions more suitable for traditional therapy. For example, even if clinical depression is not cured, the increased mood provided by using the methods of the present invention may help improve depression. As mentioned above, the use of conventional antidepressants may be more effective. In another example, modulation of neurotransmitters acts to suppress tumor growth and / or metastasis, even if the cancer is not cured, and conventional cancer treatments and / or immune systems make cancerous growth better Can be eliminated. The therapeutic effects provided by the modulation of neurotransmitters are related, for example, to the reduction of the severity of symptoms associated with a mental state, neurological state or physiological state, mental state, neurological state and physiological state May be an eradication of symptoms or an increase in mood concealing symptoms associated with mental, neurological or physiological conditions.

  The method according to the invention can be used therapeutically to deal with an undesired mental, neurological or physiological condition of a patient. For example, the methods of the present invention may be used to treat an undesirable mental, neurological or physiological condition pre-existing in a patient, such as mood disorders, eating disorders, pain disorders, drug abuse disorders, anxiety disorders, obsessive compulsive nerves. Can be used to treat the disease. The method also mitigates any future undesirable mental, neurological or physiological condition expected to occur, for example, by future physical movements, physical trauma, mental trauma, or medical treatment Can be used to Many examples of conditions that can be addressed using the method of the present invention are described in more detail below.

(Substance P system)
According to one embodiment of the present invention, the neurotransmitter system is a substance P (“SP”) system comprising neurokinin substance P, NKA and NKB as neurotransmitters. SP is a polypeptide and is known to act as a neurotransmitter and mediator for pain sensation. SP is one of a group of tahikinins that are a collection of polypeptides having a similar C-terminus and an N-terminus that changes according to SP-like activity. SP receptors include NK-1, NK-2, and NK-3 receptors. SP selectively binds to the NK-1 receptor, NKA selectively binds to the NK-2 receptor, and NKB selectively binds to the NK-3 receptor.

  SP and its receptors are mainly found in brain and spinal cord tissue. In the spinal cord, SP receptors are found in a region called the dorsal horn, the primary site of pain signals transmitted to the brain. In the brain, SP and its receptors are found in high concentrations in the hypothalamus and amygdala, an area associated with emotional behavior, anxiety and response to stress, and pain. Furthermore, SP is associated with numerous mental states such as schizophrenia, manic depression, sexual dysfunction, drug dependence, cognitive impairment, locomotive disorders and depression, as well as nausea and vomiting, defensive behavior, It is also involved in cardiovascular tone, salivation, inflammation, smooth muscle contraction and vasodilation.

  When the neurotransmitter system is the SP system, the type of receptor is an SP receptor that is positively associated with many undesirable mental and neurological conditions, and the ligand is an SP receptor agonist. is there. Counter-adaptation causes down-regulation of the SP system, reducing SP, NKA and / or NKB biosynthesis or release, receptor number and / or binding on the receptor terminus or by the pituitary gland It may be at least one of a reduction in the number of sites or a decrease in the sensitivity of the receptor to binding by SP receptor agonists and / or SP, NKA and / or NKB.

The SP receptor agonist may be, for example, a peptide system. In certain embodiments of the invention, the SP receptor agonist is an analog of SP, NKA, and / or NKB, or a pharmaceutically acceptable salt or derivative thereof. For example, SP receptor agonists are substance P; substance P, free acid; biotin substance P; [Cys ^3,6 , Tyr ⁸ , Pro ⁹ ] -substance P; (disulfide bridge: 3-6), [Cys ^{3, 6} , Tyr ⁸ , Pro ¹⁰ ] ^-Substance P; (Disulfide bridge: 3-6), [4-Chloro-Phe ^7′8 ] ^-Substance P; [4-Benzoyl-Phe ⁸ ] ^-Substance P; [Succinyl- Asp ⁶ , N-Me-Phe ⁸ ] -Substance P (6-11) (Senstide); [Tyr ⁸ ] -Substance P; [Tyr ⁹ ] -Substance P; Shark Substance P Peptide; GR7632 [D-Ala- [ ^{L-Pro 9, Me-Leu} 8] substance ^{P (7-11)]; [Sar} 9, Met (O ) ^11] SP; GR73,632 [delta - Aminobareriru [Pro9, Ν-Me-Leu10 ] - substance P (7-11)], [Glu (OBzl) 11] substance P and Hemokinin 1 (HK-1) (Substance P homolog); or a pharmaceutically acceptable salt or carrier thereof.

In another embodiment of the invention, the SP receptor agonist is an NKA or NKB analog having a C-terminal heptapeptide similar to NKA (4-10) or NKB (4-10), or a medicament thereof. As an acceptable salt or carrier. For example, SP receptor agonists are [Gln ⁴ ] -NKA, [Gln ⁴ ] -NKA (4-10), [Phe ⁷ ] -NKA, [Phe ⁷ ] -NKA (4-10), [Ile ⁷ ]. ^{-NKA, [Ile7] -NKA (4-10} ), [Lys 5, MeLeu 9, Nle 10] -NKA (4-10), [Nle 10] -NKA (4-10), β-Ala 8] - NKA (4-10), [Ala ⁵ ] -NKA (4-10), * [Gln ⁴ ] -NKB, [Gln ⁴ ] -NKB (4-10), [Phe ⁷ ] -NKB, [Phe ⁷ ] ^{-NKB (4-10), [Ile 7} ] -NKB, [Ile7] -NKB (4-10), [Lys 5, MeLeu 9, Nle 10] -NKB (4-10), [Nle 10] -NKB (4-10), β-Al ^8] -NKB ^(4-10), may be [Ala 5] -NKB (4-10) or acceptable salt or carrier as their pharmaceutically. Similarly, the SP receptor agonist may be [Arg] -NKB, NKA or NKB analogs having Val ⁷ substituted with MePhe, or a pharmaceutically acceptable salt or carrier thereof.

  Other SP receptor agonists that can be used in the present invention are SR48968, an NK2 receptor antagonist ((S) -N-methyl-N [4- (4-acetylamino-4-[(phenylpiperidino) -2). -(3,4-dichlorophenyl) -butyl)] benzamide], and U.S. Pat. Nos. 4,839,465, 4,472,305, 5,137,873, 4,638, No. 046, No. 4,680,283, No. 5,166,136, No. 5,410,019, and No. 6,642,233. Each of which is incorporated herein by reference in its entirety.

  The initial dose of the SP receptor agonist (ie, the dose of the first dose) is desirably high enough to induce a counter-adaptive effect, but is sufficient to cause an unbearable direct effect due to ligand-receptor binding. not high. For example, the initial dose of the SP receptor agonist can be about 0.5 pmol / kg / min to about 20 pmol / kg / min for continuous administration in the first period. In certain desirable embodiments of the invention, the initial dose of the SP receptor agonist can be 3 pmol / kg / min to 10 pmol / kg / min for continuous administration in the first period.

  The present invention is not limited to the use of peptide-based SP receptor agonists. In the methods of the present invention, substantially or completely non-peptidic SP receptor agonists (eg, as described in Chorev et al., Biopolymers, May 1991, 31 (6), pages 725-33. Other SP receptor agonists may be used, including the entire contents of which are incorporated herein by reference.

  The SP receptor agonist can be administered using any suitable route. Transmucosal administration is a particularly desirable method for administering SP receptor agonists. For example, administration may be sublingual or by rectal suppositories. A rapidly absorbed loading dose (to obtain rapid binding of the SP receptor) and a gradual absorption (to maintain the desired level of agonist-receptor binding over a first period of the desired length). It may be desirable to administer the SP receptor agonist using both For such administration, rectal suppositories having a rapidly absorbing outer layer and a slower absorbing core may be used. Alternatively, a loading dose can be applied sublingually and a slowly absorbed dose can be applied transdermally via a patch. Other routes include intrathecal or spinal intrathecal administration for pain.

  Desirably, the SP receptor antagonist is not administered during the first period associated with each administration. However, in certain embodiments of the invention, the SP receptor antagonist is administered in one or more of the plurality of second time periods. Non-limiting examples of SP receptor antagonists shown with suggested dosages are as follows: SR 48968 ((S) -N-methyl-N (4-acetylamino-4-phenylpiperidino- 2- (3,4-dichlorophenyl) -butyl) benzamide); U.S. Pat. Nos. 5,972,938; 6,576,638; 6,596,692; 6,509,014 No. 6,642,240; No. 6,841,551; No. 6,177,450; No. 6,518,295; No. 6,369,074; And Osanetant and compounds described in International Publication Nos. WO95 / 16679; 95/18124; and 95/23798.

  Other SP (NK1) receptor antagonists include L-760735 ([1- (5-{[(2R, 3S) -2-({(1R) -1- [3,5-bis (trifluoromethyl) ) Phenyl] ethyl} oxy) -3- (4-phenyl) morpholin-4-yl] methyl} -2H-1,2,3-triazol-4-yl) -N, N-dimethylmethanamine]) (voice Boyce, S et al., Neuropharmacology, July 2001, 41 (1): pp. 130-7); CP-96,345 [(2S, 3S) -cis-2- (diphenylmethyl) -N -[(2-Methoxy-phenyl) -methyl] -1-azabicyclo [2.2.2] -octane-3-amine] (Snider et al., Science, 25 January 1991, 251 (4992) Pp. 435-7); SS R240600 ([(R) -2- (1- {2- [4- {2- [3,5-bis (trifluoromethyl) phenyl] acetyl} -2- (3,4-dichlorophenyl) -2-morpholinyl ] Ethyl} -4-piperidinyl) -2-methylpropanamide] (Steinberg, R. et al., J Pharm Exper Ther, 303 (3), 1180-1188, December 2002, “SSR240600 [( R) -2- (1- {2- [4- {2- [3,5- (bis (trifluoromethyl) phenyl] acetyl} -2- (3,4-dichlorophenyl) -2-morpholinyl] ethyl} -4-piperidinyl) -2-methylpropanamide], tachykinin Neurokinin 1 receptor centrally acting non-peptide antagonists: II Neurochemical and behavioral characteristics ("SSR240600 [(R) -2- (1- {2- [4- {2- [3,5- (Bis (trifluoromethyl) phenyl] acetyl} -2- (3,4-dichlorophenyl) -2- morholinyl] ethyl} -4-piperidinyl) -2-methylpropanamide], a Centrally Active Nonpeptide Antagonist of the Tachykinin Neurokinin 1 Receptor: II. Neurochemical and Behavioral Characterization))); NKP608 [quinoline-4-carboxylic acid [trans- ( 2R, 4S) -1- (3,5-bis-trifluoromethyl-benzoyl) -2- (4-chloro-benzyl) -piperidin-4-yl] -amide)] (Spooren WP) et al. , Eur J Pharmacol., January 25, 2002, 435 (2-3), pages 161-70, and File, SE, Psychopharmacology (Berl)., September 2000, 152 (1), Pp. 105-9, titled “Has anxiolytic activity in a social interaction test in rats NKP608, NKl receptor antagonist (see NKP608, an NKl receptor antagonist, has an anxiolytic action in the social interaction test in rats)); L-AT (N-acetyl-L-tryptophan 3,5-bisbenzyl ester) (Chrissman A, et al., 302, No. 2, pages 606-611, August 2002, titled “Antidepressant in trained rats identifying isopretenol administered to the central nervous system” Effects (see Effects of Antidepressants in Rats Trained to Discriminate Centrally Administered Isoproterenol)); MK-869 [Aprepitant] (Varty GB) et al. -Type cross maze II: anxiolytic-like effect of selective neurokinin NK1 receptor antagonist The Gerbil Elevated Plus-maze II: Anxiolytic-like Effects of Selective Neurokinin NKl Receptor Antagonists) ”; L-742,694 [2 (S)-((3,5-bis (trifluoromethyl) benzyl) -oxy )-(3 (S) phenyl-4-((3-oxo-1,2,4-triazol-5-yl) methyl) morpholine)] (see Varty et al.); L-733060 [(2S, 3S) 3-([3,5-bis (trifluoromethyl) phenyl] methoxy) -2-phenylpiperidine] (see Bertie et al.); CP-99,994 [(+)-(2S, 3S) -3- (2-methoxybenzylamino) -2-phenylpiperidine] (see McLean et al., J Pharm Exp Ther, Vol. 267, No. 1, pages 472-479 and Bertie et al.); CP-122,721 [ (+)- 2S, 3S) -3- (2-methoxy-5-trifluoromethoxybenzyl) amino-2-phenylpiperidine] (McLean et al., J Pharm Exp Ther, Vol. 277, No. 2, pages 900-908. CP-96,345 [(2S, 3S) -cis-2- (diphenylmethyl) -N-((2-methoxyphenyl) -methyl) -1-azabicyclo (2.2.2 . ) -Octane-3-amine (see Bang et al., J Pharmacol Exp Ther., April 2003, 305 (1), 31-9) GSK597599 [Vestipitant]; GSK679769 (hunter ( Hunter et al., U.S. Patent Publication No. 20050186245); GSK823296 (see Hunter et al., U.S. Patent Publication No. 20050186245); Saredutant (Van Schoor et al., Eur Respir J, 1998). 12: 17-23), Talnetant; Osanetant (Kamali, F, Curr Opin Investig Drugs. July 2001, 2 (7), pages 950-6); SR -489686 (benzamide, N- [4- [4- (acetylamino) -4-phenyl-1-piperidinyl] -2- (3,4-dichloro) SB-23412 (see Hunter et al. US Patent Publication No. 20050186245); SB-235375 (4-quinolinecarboxamide-, 3-hydroxy) -2-phenyl-N-[(1S) -1-phenylpropyl]-), UK-226471 (see Hunter et al. US Patent Publication No. 20050186245).

  Suitable but non-limiting initial doses of SP receptor antagonists include about 12 mg / kg / hour / 8 hours (via intravenous administration) for L-7607358 and about 30 μg / kg / hour for CP-96,345. / 8 hours (by intravenous administration), about 0.1 to 10 mg / kg / dose (by intraperitoneal or oral administration) for SSR240600, about 0.01 to 0.1 mg / kg / dose for NKP608 (oral administration) About 1-10 mg / kg / dose for L-AT, about 0.01-3 mg / kg / dose for MK-869, about 1-30 mg / kg for L-742,694, and about L-733,060 About 1-10 mg / kg / dose, about 3-30 mg / kg / dose for CP-99,994 or CP-122,721, and about 100 for salezant g / dose (by oral administration) and the like.

  The SP neurotransmitter system is positively associated with a wide variety of undesirable mental and neurological conditions. Examples of such conditions include chronic pain, mood disorders, eating disorders, anxiety disorders, motivational problems, drug abuse disorders, inflammatory conditions, nausea or vomiting (eg resulting from chemotherapy), urine Incontinence, skin rash, erythema, rash, fibromyalgia, chronic fatigue syndrome, chronic back pain and chronic headache, chronic cancer pain, shingles, reflex sympathetic dystrophy, neuropathy, inflammatory pain, in the future (eg Pain, major depression, post traumatic depression, temporary depressed mood, manic depression, dysthymic disorder, generalized mood disorder, annoyance Non-organismal dysfunction, overeating, obesity, anorexia, bulimia, generalized anxiety, panic disorder, phobia, obsessive compulsive disorder, attention deficit hyperactivity disorder, Tourette syndrome, hysterical sleep disorder, breathing Related sleep disorders Lack of motivation due to learning or memory impairment, abuse of drugs such as narcotics, alcohol, nicotine, stimulants, anxiolytics, central nerve suppressants, hallucinogens and marijuana, asthma, arthritis, rhinitis, conjunctivitis, inflammatory bowel disease , Skin or mucous membrane inflammation, acute pancreatitis. Down-regulation of the SP system desirably provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions.

  In fact, all types of pain are related to the SP system with the exception of acute sharp pain. SP is not related to the initial pain caused by stabs. However, the remaining pain is due to the SP pathway. Similarly, pain remaining for a period of time after the surgical procedure is transmitted by the SP pathway.

  Mood is mediated by the SP system. Patients who are clinically depressed have elevated SP levels. Drug abusers do not use abuse substances and generally have increased SP levels when they are depressed and / or uncomfortable. Thus, both clinical depression and drug abuse are associated with SP system upregulation. In mice lacking the SP receptor, a pleasant experience with morphine does not occur. Such mice do not become morphine addicted (Murtra et al., Nature 405, pp. 180-183, May 11, 2000). Since opiates (opiates) alone cannot induce euphoria, Matra's studies suggest that the SP system is the final pathway through which opiate euphoria is mediated. The fact that SP antagonists can improve mood acutely is consistent with this finding. Anxiety, response to stress, sexual dysfunction and eating disorders are influenced by the SP system because they are primarily related to mood.

  The SP system also includes asthma (Kudlacz EM), “Combined tachykinin receptor antagonists for the treatment of respiratory diseases”, Expert Opinion on Investigational Drugs, Vol. 7, No. 7, July 1998, pages 1055-1062), nausea / vomiting, cancerous tumor growth and metastasis (Palma, C. et al., Br. J. Cancer, January 1999, 79 (2), 236-43, and Friess et al., Lab. Invest., May 2003, 83 (5), 731-42), and urinary incontinence (Andersson KE), Experimental Physiology, Vol. 84 (1), pp. 195-213).

  The methods of the invention using an SP receptor agonist as a ligand can be used to address an undesired mental, neurological or physiological condition in a patient. For example, the method of this embodiment of the invention may be used to address any of the conditions listed above. The method according to this embodiment of the invention may also be used as an adjunct therapy for cancer (eg, to reduce tumor growth and metastasis).

  In chronically repetitive pain situations such as migraine, the methods of the invention can also be used with SP agonists. Similarly, since the SP system is upregulated in chronic pain syndromes, those chronic pain syndromes may be treated using the methods of the invention having SP agonists. Such chronic pain syndromes include nerve injury, neuropathy, chronic low back pain, reflex sympathetic dystrophy, cancer pain, shingles and pain due to arthritis.

  The methods of the invention can be used with SP agonists in the prevention of pain prior to pain-related events. The method of the present invention may be used to reduce post-operative pain and may further be used to increase post-operative response to anesthetic analgesics, thereby obtaining an analgesic effect. Anesthetic dose is reduced. Similarly, SP agonists may be used in the methods of the present invention prior to competitive competitions such as football, hockey and boxing. SP agonists may be used to reduce the perception of pain unavoidable in such muscle and leg overuse before any competitive competition, such as long distance running. The reduced pain response ultimately allows the competitor to work harder to his higher limits, resulting in improved performance.

  The methods of the invention may also be used with SP agonists to address anxiety, stress responses, sexual dysfunction and eating disorders that can be improved with SP agonist CAT protocols. Involved. Thus, improvements in these conditions are indirectly related to overall mood as opposed to direct effects.

  The methods of the invention can also be used with SP agonists to address any or all addictive disorders. For example, the methods of the invention can be used to combat the abuse of drugs such as anesthetics, alcohol, nicotine / cigarettes, stimulants, anxiolytics, central nervous depressants, hallucinogens and marijuana. Furthermore, gambling and electronic gambling addiction occurs as a result of the same brain abnormalities that cause drug abuse problems and can be addressed using the methods of the present invention.

  The methods of the invention may also be used with SP agonists to combat asthma by reducing the severity of asthma attacks. The route of administration by inhalation is used to concentrate the counter-adaptive effect in the lungs where it is most needed. The methods of the invention also provide SP agonists to reduce inflammatory responses in any one of a number of inflammatory conditions such as arthritis, rhinitis, conjunctivitis, inflammatory bowel disease, skin and mucosal inflammation, and acute pancreatitis. Can be used together. The methods of the invention can also be used with SP agonists to address nausea / vomiting, particularly nausea / vomiting associated with chemotherapy for cancer, and urinary incontinence.

(Endogenous endorphins)
According to another embodiment of the present invention, the neurotransmitter system is an endogenous endorphin system comprising endorphins that selectively bind mu and / or delta opiate receptors as neurotransmitters. Endorphins are endogenous opiate-like compounds that act through their effects on opiate receptor binding. Mu and delta-opiate receptors act in concert and are stimulated by opiates and opiate-like compounds. Mu receptors primarily modify pain but also modify mood. Delta receptors have the opposite focus and primarily modify mood, but also modify pain.

  When the neurotransmitter is the endogenous endorphin system, the kind of receptor is a mu and / or delta opiate receptor. These receptors are generally negatively associated with undesirable mental and neurological conditions. Mu opiate receptors are primarily associated with lower levels of pain when stimulated, whereas delta opiate receptors are primarily associated with euphoria when stimulated. The ligand is a mu and / or delta opiate receptor antagonist and counteradaptation results in an upregulation of the endogenous endorphin system. Counter-adaptation may be, for example, increased endorphin biosynthesis or release at the receptor terminus and / or by the pituitary, increased number of receptors and / or endorphin binding sites on the receptor, mu and / or Or it may be an increase in the sensitivity of the receptor to binding by delta receptor agonists and / or endorphins, or a combination thereof.

  The method according to this embodiment of the invention may be practiced using a specific mu receptor antagonist or a specific delta receptor antagonist. Such methods include, for example, clocinnamox mesylate, CTAP, CTOP, etonitazenyl isothiocyanate, β-funaltrexamine hydrochloride, naloxonazine dihydrochloride, cyprodim (Cyprodime), and specific mu receptor antagonists such as their pharmaceutically acceptable salts, analogs and derivatives. The method also includes naltrindole, N-benzylnaltrindole HCl, BNTX maleate, BNTX, ICI-154,129, ICI-174,864 (N, N-diallyl). -Tyr-Aib-Aib-Phe-Leu-OH, wherein Aib is α-aminoisobutyric acid), naltriben mesylate, SDM25N HCl, 7-benzylidenenaltrexone, and pharmaceuticals thereof May be carried out using specific delta receptor antagonists such as acceptable salts, analogs and derivatives. One skilled in the art may also use non-specific mu and / or opiate antagonists such as naloxone and naltrexone in the methods according to this embodiment of the invention. Non-limiting representative examples of non-specific opiate antagonists include narolphine, nalbuphine, levalorphin, ticlazosin, diprenorphine.

  Other mu and / or delta opiate receptor antagonists that can be used in the methods of the present invention are US Pat. Nos. 5,922,887, 4,518,711, 5,332,818, 6,790,854, 6,770,654, 6,696,457, 6,552,036, 6,514,975, 6,436, No. 959, No. 6,306,876, No. 6,271,239, No. 6,262,104, No. 5,552,404, No. 5,574,159, No. 5,658,908, 5,681,830, 5,464,841, 5,631,263, 5,602.99, 5,411,965 No.5,352,680 No.5,332,81 No. 4,910,152, No. 4,816,586, No. 4,518,711, No. 5,872,097, No. 5,821,219, No. 5 No. 4,326,751, No. 4,421,744, No. 4,464,358, No. 4,474,767, No. 4,476,117, No. 4,468,383. 6,825,205, 6,455,536, 6,740,659, 6,713,488, 6,838,580, 6, 337,319, 5,965,701, 6,303,578, 4,684,620, and international patent application WO / 2004/026819. Each of the above patent documents is incorporated herein by reference in its entirety.

  In certain desirable embodiments of the invention, the mu and / or delta opiate receptor antagonist is naloxone, naltrexone, nalmefene or nalbuphine, or a pharmaceutically acceptable salt or derivative thereof. Naltrexone is a desirable mu and / or delta receptor antagonist, but may not be usable in all situations due to its long compound half-life (48-72 hours). Naltrexone itself has a half-life of 9-10 hours, but its active metabolites (eg, 6-beta-naltrexol and 2-hydroxy-3-methoxynaltrexol (2-hydroxy) -3-methoxynaltrexol)) has a much longer half-life. Naloxone is a particularly desirable mu and / or delta receptor antagonist for use in this embodiment of the invention. Naloxone has a compound half-life of about 1 hour but cannot be administered orally. Naloxone can desirably be administered intravenously or by transdermal patch using a time-release formulation. A suitable transdermal patch is described in US Pat. No. 4,573,995. This patent document is incorporated herein by reference in its entirety.

  Naloxone has a half-life of 1 to 1.5 hours and is suitable for use in the method of the present invention. A half-life of 1 to 1.5 hours is suitable for inducing a counter-adaptive response, but ligands more preferred for use in the present invention have a half-life of 2 to 4 hours. In addition, naloxone is not very convenient for outpatient administration because its oral bioavailability is as low as 5%.

  Thus, in one aspect, the invention provides 3-hydroxy as a mu and / or delta opiate antagonist ligand that can be administered orally and has a longer half-life than native naloxone and a shorter half-life of naltrexone or nalmefene than 8 hours. Methods are provided for using morphinans, and derivatives and prodrugs thereof. Preferred compounds have a half-life in the range of 4 hours or less, if desired 2 to 4 hours. Optionally, 3-hydroxymorphinan as a mu and / or delta opiate antagonist ligand may be administered by the transmucosal route.

  The bioavailability of the 3-hydroxymorphinan compound may be increased by use of a prodrug formulation. The prodrug formulations of the invention herein have a chemical group attached to the original 3-hydroxymorphinan compound to prevent the first pass metabolic step of rapidly glucuronidating the 3-OH moiety. . The attached chemical groups for the invention herein are non-toxic. In addition, the attached chemical groups are those that are removed within a period of time, and the overall compound half-life of the mu and / or delta opiate antagonist ligand remains less than 4 hours.

  Some of the 3-hydroxymorphinan compounds described herein used in the present invention have high lipophilicity. High lipophilicity increases transmembrane absorption and improves oral and transmucosal administration possibilities. The result is more rapid and efficient transport at the blood-brain barrier. Such improved transport across the blood brain barrier is preferred to increase the counteradaptive response by mu and / or delta opiate receptor antagonists.

  Due to the fact that naloxone analogs have a relatively short half-life than other opiate antagonists, such as naltrexone or nalmefene, in desired embodiments of the invention, the mu and / or delta opiate receptor antagonist is a naloxone analog. .

Numerous naloxone prodrug chemicals are used, if desired, to achieve the objective of counter-adaptive treatment where naloxone can be administered orally and / or transmucosally to outpatients (or hospitalized patients). These prodrugs include 3-OH moieties, modified at 6-carbon, C-14 carbon and N-oxide prodrug formulations. Preferred modifications are modifications at the 3-OH and / or 6-carbon sites.
Example of 3-OH-modified morphine To demonstrate a modification that yields a more lipophilic structure and a method that favors such modification, morphine analogs are used. The morphine structure is:

である。

It is.

  When 3-OH and 6-OH groups are converted to acetyl groups, the compound becomes diacetylmorphine, otherwise known as heroin. Diacetylmorphine has properties that are favorable to morphine, which is more lipophilic and is therefore more rapidly and efficiently absorbed through the mucosal surface. For example, oral administration availability of morphine is @ 25-30% (Hasselstrom, J et al., Clin. Pharmacokinet. 1993 Apr; 24 (4): 344-54, and Gourlay, GK, et al. 1986 Jun; 25 (3): 297-312), the availability of oral administration of diacetylmorphine is 67% (Girardin, F. et al., “Pharmacokinetics of high doses of intranuscular and oral heroin in narcotic). addicts. "Clin Pharmacol Ther. 2003 Oct; 74 (4): 341-52). Moreover, the diacetyl derivative more easily crosses the blood brain barrier.

  In naloxone compounds, similar lipophilicity occurs when the 3-OH group is converted to a 3-acetylnaloxone derivative. This increases lipophilicity and provides significant benefits over the original naloxone compounds, such as improved bioavailability, high capacity, and prolonged duration of action on 3-acetylnaloxone. These benefits were demonstrated by Linder and Fishman ("Narcotic Antagonists. 1 ..." J Medicinal Chemistry, 1973, 16 (5): 553).

  If the carbon chain is further extended, such as by converting 3-OH to 3-propanyl, 3-butanoyl, 3-hexanoyl, etc., the lipophilicity is further enhanced. For example, for 3,5-diesters of morphine, the addition of such extended carbon chain groups results in comparable or higher potency and extended action time from 20% up to 5 times [Owen, JA, et al., “Morphine Diesters. I…” Can J Physiol Pharmacol. 1984 Apr; 62 (4): 446-51, and “Morphine Diesters. II…” 452-456].

The desired compound used in the present invention to improve lipophilicity, which has the effect of enhancing the counter-adaptive response, to improve oral administration availability, and to slightly increase the duration of action of the naloxone compound, is similar to naloxone. 3-OH acetyl, butanoyl, propanoyl and hexanoyl derivatives.
Naltrexone example:
Naltrexone is similar to the structure of naloxone, the only difference being the N-part. These differences are shown in the following figure.

ナルトレキソン化合物の３−ＯＨ修飾を分析することにより、３−ヒドロキシモルフィナンの高い経口投与利用性を実証することができる。具体的には、ベンゾアート類似エステルからなるナルトレキソン化合物の３−ＯＨ修飾体は、生物学的利用性が高いことが実証された。例えば、生物学的利用性は、ナルトレキソンのアセチルサリチラートおよびアントラニラートエステルでは、それぞれ本来のナルトレキソン化合物に比較して２８〜４５倍高い（Ｈｕｓｓａｉｎ ＭＡ， ｅｔ ａｌ．， Ｊ． Ｐｈａｒｍ Ｓｃｉ． １９８７ Ｍａｙ；７６（５）：３５６−８；Ｈｕｓｓａｉｎ ＭＡ， ｅｔ ａｌ．， Ｐｈａｒｍ Ｒｅｓ． １９８８ Ｆｅｂ ５（２）：１１３−５；ＵＳ４，６６８，６８５およびＵＳ４，６７３，６７９を参照）。ナルトレキソンのこれらのプロドラッグの代謝副産物は、アントラニル酸およびアセチルサリチラートである。アントラニル酸は、アミノ酸トリプトファンの通常の代謝副産物である。アセチルサリチル酸は、アスピリンとしてより公知である。これらの副産物は両者とも、対抗適応を誘導するのに必要な用量では、安全で非毒性であると判断される。

By analyzing the 3-OH modification of the naltrexone compound, the high oral dosage availability of 3-hydroxymorphinan can be demonstrated. Specifically, it has been demonstrated that a 3-OH modified form of a naltrexone compound comprising a benzoate-like ester has high bioavailability. For example, bioavailability is 28-45 times higher for acetyl salicylate and anthranilate esters of naltrexone compared to the original naltrexone compound (Hussain MA, et al., J. Pharm Sci. 1987). May; 76 (5): 356-8; Hussain MA, et al., Pharm Res. 1988 Feb 5 (2): 113-5; see US 4,668,685 and US 4,673,679). Metabolic byproducts of these prodrugs of naltrexone are anthranilic acid and acetylsalicylate. Anthranilic acid is a common metabolic byproduct of the amino acid tryptophan. Acetylsalicylic acid is more known as aspirin. Both of these by-products are considered safe and non-toxic at the doses required to induce counter-adaptation.

Accordingly, in desired embodiments of the present invention, such anthranilate acetylsalicylate 3-OH prodrug modified naloxone compounds are used in the methods described herein. Moreover, based on the high lipophilicity of the carbonyl bond at the 3-OH site and improved oral bioavailability, in another desired embodiment of the invention, an alkanoyl (2-6 carbon atoms) prodrug modified naloxone The compounds are used in the methods described herein.
Carbon-6 Modification In certain desired embodiments of the invention, the methods described herein are practiced with 6-carbon modified naloxone derivatives. One such modification is, for example, from the original 6- = O compound to 6-deoxy, 6-methylene, as described in US Pat. No. 3,814,768 and US Pat. No. 4,535,157. Including conversion to the derivative (6-═CH ₂ ).

The 6-methylene modification is preferred in order for such conversion to provide multiple benefits. These include increasing the effect at the opiate receptor, improving oral dosage availability, and making the molecule more lipophilic. These benefits were demonstrated when a 6-═CH ₂ substitution was made on the naltrexone molecule resulting in a compound called nalmefene. Nalmefene, a 6-methylene naltrexone analog, has several reasons: 1) higher bioavailability, 2) longer antagonism, 3) more competitive binding to opioid receptors [To produce a larger counteradaptive response], and 4) have improved properties over naltrexone due to the fact that liver toxicity is not dose-dependent [Mason, BJ, et al, Arch Gen Psych 1999, Aug; 56 (8): 719-24 and Dixon, R, et al, J Clin Pharm 1987; 27: 233-239].

A further example of improved receptor activity with 6-═CH ₂ substitution is demonstrated by the 6-methylene derivative of morphine. Such analogs are 75 times more potent than the parent morphine compound (Hahn and Fishman, J Med Chem. 1975, 18 (3): 259). Hahn and Fishman have further shown that the 6-methylene naloxone derivatives have significantly better oral performance than the original naloxone compounds.

Other such modifications include conversion of the original 6-═O compound to a 6-desoxy compound (ie, 6-(— H) ₂ ) analog. The 6-desoxy modification has multiple potential benefits over the 6-═O group. First, it makes the compound more lipophilic. Second, it increases opiate receptor activity. For example, 6-deoxymorphine has 10 times the activity of the original morphine compound. Similarly, 6-deoxynaloxone has higher antagonist activity than the original naloxone compound (see Table 1, Materials & Methods, Minakami, et al., Life Sciences 1962, 10; 503-507). Thirdly, it is intended for a slight extension of the active period, ie the half-life.

  Other such modifications include conversion of the original 6- = O compound to a 6-OH, 6-amine or 6-amide analog. US Pat. No. 6,713,488 describes “neutral antagonists” in which modifications are made at the 6-carbon group. These compounds are called “neutral” because the 6-carbon ketone group is converted to an —OH functional group or an amine or amide.

Simultaneous modification may be performed at both the 3-OH and 6-C = O sites. Such dual modifications are intended to further enhance oral dosage availability and counter-adaptive response. For example, anthranilic acid 3-OH substitution increases oral administration availability by a factor of 45, and conversion of a 6-C = O group to either a 6-methylene or 6-desoxy moiety also increases oral administration availability, If the two (3-OH and 6C modifications) are taken together, it is expected that oral administration availability will be further enhanced. In addition, the two substitutions further improve transport efficiency across the blood-brain barrier and have the effect of increasing opiate receptor activity, both of which have the effect of increasing the counteradaptive response, thus improving clinical efficiency.
Other modified N-oxide derivatives of 3-hydroxymorphinan can also be used in the methods of the invention. Such derivatives are described in US Pat. Nos. 4,722,928 and 4,990,617.

  Derivatives of hydroxymorphinan having a substituent at 14-carbon can also be used in the method of the present invention. U.S. Pat. No. 4,912,114 and U.S. Pat. No. 4,272,540 are hereby incorporated by reference and describe 3-hydroxymorphinan compounds substituted with a 14-carbon group.

  Thus, in certain embodiments of the invention the mu and / or delta opiate receptor antagonist is a structure

（式中、Ｒは、アリル、メチルアリル、シクロプロピルメチル、ジメチルアリル、テトラヒドロフルフリル、またはシクロブチルメチルであり、Ｒ^１は、Ｈ、（Ｃ_１〜Ｃ_１８ヒドロカルビル）−、（Ｃ_１〜Ｃ_１８ヒドロカルビル）−ＣＯ−、（Ｃ_１〜Ｃ_１８ヒドロカルビル）_２Ｎ−ＣＯ−、（Ｃ_１〜Ｃ_１８ヒドロカルビル）−ＳＯ_２−、（Ｃ_１〜Ｃ_１８ヒドロカルビル）−Ｏ−ＣＯ−、Ｐｈ−ＣＯ−、Ｐｈ−ＳＯ_２−、Ｐｈ−ＮＨ−ＣＯであり、各Ｐｈは、（Ｃ_１〜Ｃ_１２ヒドロカルビル）、（Ｃ_１〜Ｃ_１２ヒドロカルビル）−Ｏ−、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＦ_３、Ｒ^４Ｏ−、およびＲ^４ _２Ｎ−からなる群から独立して選択される一以上の置換基で任意に置換されており、各Ｒ^４は、Ｈ、（Ｃ_１〜Ｃ_４アルキル）、Ｈ−ＣＯ−および（Ｃ_１〜Ｃ_４アルキル）−ＣＯ−からなる群から独立して選択され、各Ｒ^２ａおよびＲ^２ｂは、Ｈ、（Ｃ_１〜Ｃ_６アルキル）、（Ｃ_１〜Ｃ_６アルキル）−Ｏ−、（Ｃ_１〜Ｃ_６アルキル）−ＣＯ−Ｏ−、Ｒ^５−Ｏ−、Ｒ^５ _２Ｎ−、Ｒ^５−ＣＯ−ＮＨ−、Ｒ^５−Ｓ−、およびＮＯ_２からなる群から独立して選択され、各Ｒ^５は、Ｈ、（Ｃ_１〜Ｃ_６アルキル）、（Ｃ_３〜Ｃ_１０シクロアルキル）、（Ｃ_６〜Ｃ_１０アリール）（Ｃ_１〜Ｃ_６アルキル）−ＣＯ−、（Ｃ_３〜Ｃ_１０シクロアルキル）−ＣＯ−、（Ｃ_６〜Ｃ_１０アリール）−ＣＯ−、からなる群から独立して選択され、R^５はそれぞれ、（Ｃ_１〜Ｃ_１２ヒドロカルビル）、（Ｃ_１〜Ｃ_１２ヒドロカルビル）−Ｏ−、Ｃｌ、Ｆ、Ｂｒ、Ｉ、ＣＦ_３、Ｒ^４Ｏ−、およびＲ^４ _２Ｎ−からなる群から選択される１〜３個の置換基で任意に置換されているか、あるいはＲ^２ａおよびＲ^２ｂが一緒になってＯ＝もしくはＣＨ_２＝を形成し、Ｒ^３は、Ｈ、ＯＨ、ＣＨ_３、またはＯＣＨ_３である）を有する３−モルフィナン化合物、またはそのＮ−オキシドもしくは医薬として許容され得る塩である。これらの化合物は、本明細書に参考として援用された表題「ＯＰＩＡＴＥ ＡＮＡＴＯＧＯＮＩＳＴＳ ＦＯＲ ＣＯＵＮＥＲＡＤＡＰＴＡＴＩＯＮ ＴＨＥＲＡＰＹ」の米国仮特許出願番号６０／８６８，１８６に詳細に記載されている。

Wherein R is allyl, methylallyl, cyclopropylmethyl, dimethylallyl, tetrahydrofurfuryl, or cyclobutylmethyl, and R ¹ is H, (C ₁ -C ₁₈ hydrocarbyl)-, (C ₁ -C _{18 hydrocarbyl) -CO -, (C 1 ~C} 18 _{hydrocarbyl) 2 N-CO -, (} C 1 ~C 18 _{hydrocarbyl) -SO 2 -, (C 1} ~C 18 hydrocarbyl) -O-CO-, Ph- _CO-, Ph-SO 2 _-, a Ph-NH-CO, the Ph _{is, (C} 1 _{~C 12 hydrocarbyl), (C} 1 _{~C 12} hydrocarbyl) -O-, Cl, F, Br , I, It is optionally substituted with one or more substituents independently selected from the group consisting of CF ₃ , R ⁴ O—, and R ⁴ ₂ N—, wherein each R ⁴ is H, (C ₁ -C ₄ Alkyl) H-CO- and _(C 1 -C ₄ alkyl) independently from the group consisting of -CO- selected, each ^{R 2a} and ^{R _2b,} H, _(C 1 _{~C 6 alkyl), (C} 1 -C _{6 alkyl) -O -, (C 1 ~C} 6 _{^{alkyl) -CO-O-, R 5 -O-}} , R 5 2 N-, R 5 -CO-NH-, R 5 -S-, and NO ₂ Each R ⁵ is independently selected from the group consisting of H, (C ₁ -C ₆ alkyl), (C ₃ -C ₁₀ cycloalkyl), (C ₆ -C ₁₀ aryl) (C ₁ -C ₆ ). _{alkyl) -CO -, (C 3 ~C} 10 _{cycloalkyl) -CO -, (C 6 ~C} 10 aryl) -CO-, are independently selected from the group consisting of each R ⁵ is, _(C 1 ~ C _{12 hydrocarbyl), (C} 1 _{~C 12} hydrocarbyl) -O-, Cl, F, Br , I CF _3, ^R 4 O-, and ^R ₄ 2 N-optionally or substituted with 1-3 substituents selected from the group consisting of or ^{R 2a} and ^{R 2b} together O = or Is a 3-morphinan compound having CH ₂ ═ and R ³ is H, OH, CH ₃ , or OCH ₃ , or an N-oxide or pharmaceutically acceptable salt thereof. These compounds are described in detail in US Provisional Patent Application No. 60 / 868,186, entitled “OPIAATE ANATOGONITS FOR COUNTERADAPTATION THERAPY”, incorporated herein by reference.

A compound having the above structure may be desirable because it can be formulated so that the compound has a half-life longer than naloxone and 2 to 4 hours shorter than naltrexone. Further, since substitution with 3-OH (ie, a compound containing R ¹ instead of H) blocks the metabolic reaction with 3-OH, it is possible to give a compound that has higher oral availability than naloxone. it can. Therefore, these compounds may be formulated in a simpler oral dosage form. The R ¹ moiety is preferably non-toxic when cleaved from 3-OH to form the corresponding alcohol, acid or amide. The compound is formulated to have greater lipophilicity, which can enhance transmembrane absorption, improve oral and transmucosal availability, and enhance transport across the blood-brain barrier. You may let them.

  Synthetic methods for producing compounds having the above structures are known in the art, for example, US Pat. Nos. 5,366,979, each incorporated herein by reference; No. 488; No. 6,784,187; No. 4,912,114; No. 4,272,540; No. 4,322,426; No. 4,722,928; 4,990,617; 4,673,679; 4,668,685; 6,569,449; 4,535,157 and 5,908,846 And US Provisional Patent Application No. 60/813, entitled “ORALLY AVAILABLE NALOXONE DERIVATES AND METHODS OF SYNTHESIS” filed on June 15, 2006. From the method described in No. 45, it may be found by those skilled in the art.

In certain embodiments of the invention, R is allyl. Compounds where R is allyl tend to have a desirably short compound half-life.
In certain embodiments of the invention, R ¹ is not H. For example, R ¹ may be o-aminobenzoyl or o- (acetyloxy) benzoyl. R ¹ may be (C ₁ -C ₁₈ alkyl) or (C ₁ -C ₁₈ alkyl) CO—. One particularly desirable value for R ¹ is (C ₁ -C ₅ alkyl) CO—. As used herein, a (C _n -C _m alkyl) group is a straight or branched alkyl chain having _n to _m carbon atoms.

In certain embodiments of the invention, R ^2a and R ^2b are not taken together to produce O═. Such compounds are more compatible and have greater opiate receptor activity than naloxone compounds. For example, R ^2a and R ^2b may each be H or taken together to form CH ₂ ═.

In certain particularly desirable embodiments of the invention, R ¹ is not H and R ^2a and R ^2b are not taken together to produce O =. Such compounds have particularly high oral administration availability and blood-brain barrier transport.

In certain embodiments of the invention, R ³ is not OH.
An example of a suitable delta receptor selective antagonist is the structure:

を有する。

Have

  The initial dose of mu and / or delta opiate receptors is desirably high enough to induce counteradaptive effects, but not high enough to produce a direct effect that is unbearable to the patient. For example, the initial dose of mu and / or delta opiate receptor antagonist may correspond to about 2 mg / dose to about 200 mg / dose for naloxone. In certain desirable embodiments of the invention, the initial dose of mu and / or delta opiate receptor antagonist may correspond to about 10 mg / dose to about 100 mg / dose for naloxone.

  When using naloxone as a mu and / or delta opiate receptor antagonist, the initial dosage may be 5 to 500 mg / dose. Desirably, the initial dosage is 10-50 mg / dose. In certain embodiments of the invention, each dose of naloxone is greater than 10 mg / dose, greater than 10.5 mg / dose, greater than 11 mg / dose, or greater than 15 mg / dose. Desirably, the initial amount of naloxone is at least about 30 mg / dose (over 8 hours) because this amount results in complete blockade of the opiate receptor. Desirably, the maximum dose of naloxone is 3000 mg / dose or less.

  In one example of a daily dosing regimen for naloxone, the initial dose of naloxone is 30 mg / 8 hours. After 2 weeks, the dose is doubled. After an additional 2 weeks, the dose is increased to 120-160 mg / dose. Further, after 1 month, the dose is increased to 300 mg / dose, and then further increased to 500-600 mg / dose after 2 months. After a further 2 months, the dosage is increased to 1000 mg / dose and then further increased to 1500-2000 mg / dose after 2 months. Alternatively, much larger initial doses (e.g., 100-500 mg / dose) can be used to increase counter-adaptation more quickly. Low doses (eg, 10-25 mg / dose) of naltrexone can be used with naloxone to achieve additional counter-adaptation effects.

  In one example of a dosing regimen for naltrexone, an initial dose of 10-25 mg naltrexone is administered daily. Instead, larger doses (eg 25-200 mg / dose) are administered once, twice or three times a week. With larger doses of naltrexone, the first period is relatively long and sometimes overlaps with the time the patient is awake.

  Mu and / or delta opiate receptor antagonists are administered orally, transdermally, intrathecally, intrathecally, intrathecally, inhaled, subcutaneously, intravenously, intramuscularly, or transmucosally Or may be administered by osmotic pumps, microcapsules, implants or suspensions. In certain embodiments of the invention (eg, where mu and / or delta opiate receptor antagonists have a relatively short compound half-life), a time-release or slow release to provide a sufficiently long dosing half-life. It may be desirable to administer the receptor antagonist using a releasable dosage form or transdermally (eg, using a patch). When mu and / or delta opiate receptor antagonists are administered transdermally or are administered using a timed release or sustained release dosage form, those receptor antagonists desirably are 2 Release over a duration of 12 hours, 2-6 hours, or 6-12 hours. It may be desirable to administer mu and / or delta opiate receptor antagonists using a rapidly absorbed loading dose to provide a high in vivo concentration of the ligand in a short time. Use both rapidly absorbed loading and transdermal or sustained or sustained release formulations to provide high in vivo concentrations of the ligand quickly as well as to provide the desired long dosing half-life Sometimes it is desirable. A transdermal patch for naloxone, naltrexone and nalbuphine is shown in US Pat. No. 4,573,995, which is hereby incorporated by reference in its entirety. The invention herein further encompasses the simultaneous use of oral and transmucosal opiate antagonist administration routes. This is because it is desired to circulate the opiate antagonist compound at a slightly higher level by transmucosal use. When using one of the aforementioned prodrugs, such administration also results in an immediate high concentration of the intracranial opiate antagonist. This rapid high level of opiate antagonist is important when it is desired to induce an optimal counteradaptive response.

  Another aspect of the invention relates to the choice that oral administration of the opiate antagonist can be combined with transmucosal administration. Because transmucosal administration provides rapid circulating levels that persist for a short time, but oral compounds gradually become circulating levels, this dosage form allows relatively high circulating levels of opiate antagonist compounds to be used for longer periods of time. That is, to keep circulating for a maximum of 8 hours. For example, when the original naloxone molecule or 3-OH acetyl modified is administered by the transmucosal route, these compounds have essentially a half-life of 1-1.5 hours, so the effect is 2-4 hours in circulation. It only lasts. Oral naloxone analogs prolong the high circulation level of naloxone for a longer time because opiate antagonist effects last longer, for example, up to 8 hours—that is, the time spent sleeping—maximizes the counteradaptive response. Is done. In other words, doses administered by the transmucosal route are intended to rapidly reach the circulatory level and sustain it for a short time, whereas oral administration will maintain the circulatory level for up to 8 hours.

  Another aspect of the invention relates to the use of various routes of administration. For example, the start of treatment with one of the above-mentioned 3-hydroxymorphinan compounds may be selected depending on the transmucosal route of administration. This is done with lower doses of compounds to reduce acute side effects. After a period of time, it may be switched to oral administration, in which case a larger dose is more practical and by that time the patient can adapt to the side effects.

  In certain embodiments of the invention, it may be desirable to administer both a specific mu and / or delta opiate receptor antagonist and a non-specific mu and / or delta opiate receptor antagonist. The two types of antagonists may be administered at about the same time or sequentially. It is desirable to administer non-specific antagonists at an early stage of the method, as non-specific antagonists generally provide greater counter-adaptation effects provided by specific mu or delta opiate antagonists.

  Since the body develops resistance to anti-opiates approximately 8 days after the first dose, it may be desirable to increase the dose of mu and / or delta opiate receptor antagonists over time. For example, it may be desirable to increase the dosage over a period of 1 to 2 weeks.

  Desirably, the endorphin receptor agonist is not administered during the first period associated with each administration. However, in certain embodiments of the invention, the endorphin receptor agonist is administered in one or more of the second time periods. Suitable but non-limiting examples of endorphin agonists include opiates such as morphine, codeine, hydrocodone, fentanyl and oxycodone. Morphine may be administered at a dose of 1-20-50 mg for intravenous administration (iv), or transdermal, intravenous, subcutaneous (SQ), intramuscular (IM), or pump Continuous release by any suitable means such as may be administered at a dose of 1-50 mg / hour. Fentanyl can be administered at a dosage of 0.1 to 0.5 mg for 8 hours sustained release administration by any suitable means such as transdermal, subcutaneous, intramuscular or pump. Codeine can be administered at an oral dose of 10-100 mg per 4-6 hours. Hydrocodone can be administered at an oral dosage of 5-25 mg per 4-6 hours. Oxycodone can be administered by any suitable means such as sustained release transdermal, intramuscular or subcutaneous administration over a period of 4-8 hours at an oral dose of 5-100 mg per 4 hours.

  Amino acid sequence of H-Tyr-Gly-Gly-Phe-Met-OH or H-Tyr-Gly-Gly-PheLeu-OH, or any active analog of these amino acid sequences with a pharmacologically acceptable carrier Having an enkephalin. Enkephalin can be administered at a dose of 1.0 μg / hour for continuous release (transdermal administration, intravenous administration, subcutaneous administration, intraperitoneal administration (i.p.), intramuscular administration, infusion pump).

  Beta-endorphin (31 amino acid peptide) or any active analogue, eg beta-endorphin- (1-26), [D-Ala2] β-endorphin, with a pharmacologically acceptable carrier, or [ Leu5] β-endorphin. Beta-endorphin can be administered at a dose of 1.0 μg / hr for continuous release (eg, transdermal, intravenous, subcutaneous, intraperitoneal, intramuscular, infusion pump).

  A mu-selective agonist such as Carfentanil that can be administered at a dosage of 1-25 μg / kg; having [D-Ala2, NMe-Phe4, Gly-ol5] enkephalin and a pharmacologically acceptable carrier Any active analog. Enkephalin can be administered at a suggested dose of 1.0 μg / hr for continuous release (eg, intravenous, intramuscular, subcutaneous, pump, or transdermal).

Delta selective agonists such as DPDPE ([D-Pen2, D-Pen5] enkephalin), SB-235863, and SNC80. DPDPE can be administered at suggested doses of 1.0 to 5.0 μg / hr for continuous release (eg, intravenous, intramuscular, subcutaneous, pump, or transdermal). SB-235863 ([8R- (4bS ^* , 8aα, 8aβ, 12bβ)] 7,10-dimethyl-1-methoxy-11- (2-methylpropyl) oxycarbonyl 5,6,7,8,12,12b- Hexahydro- (9H) -4,8-methanobenzofuro [3,2-e] pyrrolo [2,3-g] isoquinoline hydrochloride) can be administered at an oral dose of 70 mg / kg. See Paola Petrillo et al., J. Pharmacology and Experimental Therapeutics, October 9, 2003; DOI: 10.1124 / jpet.103.055590. SNC80 can be administered at a dose of 50-75 mg / kg for sustained release administration over several hours (transdermal administration, intraperitoneal administration, subcutaneous administration, pump, etc.). See EJ Bilsky et al., Pharmacology and Experimental Therapeutics, Vol. 273, Issue 1 (pp. 359-366, 04/01/1995).

  It may be desirable to administer a CRF receptor antagonist during the second phase. Suitable CRF receptor antagonists include R121919, DMP696, antalalmine, CP-154,526, SSR125543A, 2-arylamino-4-trifluoromethylaminomethylthiazole antagonists, astresin, α-helical CRF compounds, and US Pat. No. 5,132,111; No. 5,278,146; No. 5,824,771; No. 5,844,074; No. 6,214,797; No. 6,670,371 Nos. 6,812,210 and 6,953,838, each incorporated herein by reference, and pharmaceutically acceptable salts and analogs thereof And derivatives. The CRF system is described in more detail below.

  CRF receptor agonists are administered in combination with mu and / or delta opiate receptor antagonists such that each dose has a dose half-life and the ratio of dose half-life to the period between doses is ½ or less Sometimes it is desirable. Suitable CRF receptor antagonists include analogs of corticotropin releasing factor, and pharmaceutically acceptable salts and derivatives thereof.

  When CRF receptor agonists and / or AVP receptor agonists are used in conventional dosing regimens, it may be desirable to repeatedly administer the mu and / or delta opiate receptor antagonists described herein. This is desirable due to the fact that the use of CRF receptor agonists and / or AVP receptor agonists can have the unintended consequence that β-endorphin release from the anterior pituitary is down-regulated. Such a decrease in endorphin release induces adverse effects for those adverse conditions that correlate inversely with circulating endorphin levels, such as those required for amelioration of depression and anxiety. Repeated administration of opiate antagonists can have two important effects: inhibiting endorphin down-regulation by CRF receptor agonists or AVP receptor agonists, and causing upregulation of the endorphin system described above . Thus, in some embodiments of the invention, the CRF receptor agonist and / or AVP receptor agonist is administered in the second phase for each administration of the mu and / or delta opiate receptor antagonist.

  The endogenous endorphin system and its mu and / or delta opiate receptors are negatively associated with various undesirable mental and neurological conditions. Examples of such conditions include pain, mood disorders, eating disorders, anxiety disorders, craving disorders, drug abuse disorders, lack of motivation or ability, immune system related conditions, wounds in need of treatment, future (e.g. Pain, chronic pain syndrome, acute pain, fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, shingles, reflex sympathetic dystrophy Neuropathy, inflammatory pain, chronic cancer pain, major depression, post-traumatic depression, transient depressed mood, manic depression, mood dysfunction disorder, generalized mood disorder, annoyance, Non-organic dysfunction, overeating, obesity, anorexia, bulimia, generalized anxiety, panic disorder, Tourette symptoms, hysteria sleep disorder, breathing-related sleep disorder, learning or memory impairment, anesthetic, Alcohol, d Chin, stimulants, anxiolytics, central nervous system depressants, hallucinogens and drug abuse such as marijuana, lack of willingness or preparation for the intended mental or physical activity (eg physical education, athletics, learning or testing) , Immune related conditions such as infections, AIDS or cancer, and wounds in need of treatment. Upregulation of the endogenous endorphin system desirably provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions.

  The endogenous endorphin system is involved in pain because endorphins can bind to pain-mediated opiate receptors and reduce the synthesis of SP, a pain-inducing agent. Endogenous endorphins also have stress (US Pat. Nos. 5,922,361 and 5,175,144), wound healing (Vinogradov VA), Spevak SE et al., Bi and (US Pat. No. 5,395,398), Full & fulfilled: the science of eating to your soul's satisfaction, by Nan Allison, Carol Beck, Publisher: Nash Bill, Tennessee: A & B Books, (Copyright) 1998, ISBN: 0965911799), anomalies in desire (Tejedor-Real et al., Eur J Pharmacol., July 31, 1998, 354 (1): 1 -7), immune responses (Wybran, Fed Proc., January 1985, 44 (1 part 1): 92-4, and US Pat. No. 5,817,628), and Cancer (Zagon, IS et al., Cancer Lett, 1997, 112: 167-175; US Pat. Nos. 6,737,397; 6,136,780; and 4,801) 614).

  The endogenous endorphin system is also involved in mood. Happiness is the most recognizable emotional effect of opioids, giving them a high sense of well-being and comfort. Happiness is modified by endogenous endorphins. Endorphins are released through fun experiences like eating, exercising, winning games and romantic encounters. Endorphin release is thought to produce happiness as a “reward”. Such rewards act as a motivating mechanism to encourage individuals to meet nutritional and reproductive requirements. Another function of the endogenous endorphin system for mood is to reduce anxiety, especially with respect to stress responses. Lang H. Pee. (Pangides as Mediators) (Rang HP) (1995) (Rang HP) and M. M. Dale, Pharmacology, Churchill Livingstone ), New York) has been shown to release endorphins during emotional stress and act to induce euphoria so that anxiety is reduced.

  Both endogenous endorphins and synthetic opiates can induce euphoria. The difference is that endogenous endorphins are rapidly degraded at their synapse and receptor sites, so their effects are short-term. Due to the short-term effect, no tolerance or dependence is observed. Synthetic opiates such as anesthetics have a much longer reaction time. Synthetic opiates are therefore associated with dependent expression. Synthetic opiates that combine both a strong analgesic effect and little or no possibility of developing dependence have not been developed. Since endogenous endorphins have the ability to induce euphoria similar to what opiates do, it is advantageous to use endogenous endorphins to induce a refreshing mood. However, synthetic endorphins are not desirable long-term therapeutic agents, as administration of relatively large and long-term doses of synthetic endorphins may involve the development of tolerance and dependence.

  Both mu and delta opiate receptors are involved to some extent with mood. When these receptors are bound by endorphin / opiate compounds, mu receptors not only mediate pain perception but also induce euphoria. Although the role of delta receptors in pain regulation is not clear, delta receptors appear to be more closely related to euphoria. Delta receptor agonists exhibit antidepressant activity in the forced swimming assay in rats. Furthermore, evidence from animal studies indicates that the δ-opioid receptor is involved in craving activity. Their selective involvement is due to enkephalin-controlled behavior. Broom et al. (Jpn J. Pharmacol., September 2002); 90 (1): 1-6) show that the delta opiate receptor plays an important role in depression.

  The methods of the invention using mu and / or delta receptor antagonists as ligands can be used to address an undesired mental, neurological or physiological condition of the patient. For example, the method of this embodiment of the invention can be used to address any of the conditions listed above. The method according to this embodiment of the invention may also be used as an adjunct therapy for cancer.

  The methods of the invention using mu and / or delta receptor antagonists may be used to address pain that is expected to occur in the future. For example, if the patient is scheduled for elective surgery, for example within one month, the mu and / or delta opiate receptor is used to use the high dose at night in the period before surgery. The method can be implemented. After surgery, the patient will have improved response to pain with an up-regulated endogenous endorphin system. In addition, patients will require a generally lower dose of anesthetic analgesics after surgery due to the increased sensitivity of mu and / or delta opiate receptors. The method appears to be best interrupted immediately after surgery so that post-operative pain is not increased by the direct effects of receptor challenge. Once the pain has subsided, the method may be resumed within a few days to maintain a counteradaptive response.

  In the example of preoperative therapy according to the present invention, a 49 year old man is scheduled for knee reconstruction surgery within 6 weeks. The male begins by applying 200 mg of naloxone patch, 200 mg, formulated for rapid absorption over 6-8 hours as described above. To alleviate the anxiety that this induces, the man is given diazepam (1-5 mg) as an anxiolytic drug at night in addition to the naloxone patch. Two weeks after this administration, naloxone is increased to 400 mg each night. Anti-anxiety drugs are used if necessary. After another two weeks, naloxone is increased to 60-800 mg every night. Naloxone is not administered for the night of surgery and for several nights immediately following surgery. Patients are given only standard post-operative analgesics such as morphine and codeine. The dosage of these drugs is significantly reduced by upregulation of the patient's endorphin system compared to the average person undergoing this type of surgery. Alternatively, after the first 2 weeks of naloxone treatment, the same patient is given a specific mu receptor antagonist with an increased dose of naloxone to enhance upregulation of the mu receptor that modifies pain .

  The methods of the invention may be used with mu and / or delta antagonists to improve patient mood in the treatment of depression and related conditions. Initially, a non-specific opiate receptor antagonist (eg, naloxone) can be administered to elicit a counteradaptive response. Thereafter, in therapy, it may be desirable to administer specific delta opiate receptor antagonists, since delta opiate receptors are highly related to mood. Of course, mu opiate receptor antagonists can also be used, particularly when chronic pain is associated with depressed mood. When treating an already depressed patient, one of skill in the art will carefully monitor the patient for adverse effects from any sudden deterioration of mood due to antagonist-receptor binding.

  In an example of a method for treating depressed patients using the method of the present invention, a 35 year old male with a diagnosis of clinical depression has poor response to conventional antidepressant drugs and has side effects. Was. The man is especially examined for the possibility of temporary worsening of depression, including a suicide tendency. In the initiation of treatment for patients who are potentially at risk of committing suicide, treatment by hospital or appropriate psychiatric hospital admission is considered. After this is done, the patient is started on a counter-adaptive therapy protocol with the non-specific opiate antagonist naloxone. A transmucosal naloxone formulation is started before bedtime using a 20 mg loading dose. At the same time, a 30 mg transdermal dose formulated to be absorbed over 6 hours is applied. This 8 mg dose is given for 2 weeks. In 2 weeks, the transmucosal dose is increased to 50 mg. The transdermal dose for 6 hours is 50 mg, for a total of 100 mg. This dose is given over a month. For 6 weeks after the start of treatment, the loading dose is 100 mg transmucosal dose and the transdermal dose for 6 hours is 100 mg. After an additional 4-6 weeks, it is increased to 250 mg for the loading dose and 250 mg for the 6 hour dose, for a total of 500 mg. After an additional 2 months, this dose is increased to 500 mg for the loading dose and 500 mg for the subsequent 6 hour dose. After another month, 2 months, or 3 months, the dosage is increased to 1000 mg for the loading dose and 1000 mg for the 6 hour transdermal administration. The maximum dose can be maintained over this long period at this 2000 mg total dose. Alternatively, the dose can be continuously increased to 2,500 mg, 3,000 mg, or 4,000 mg after the following year. Once a good clinical response is obtained, or the side effects become too great, or if hematology shows an increase in liver function enzymes, the maximum dose reaches a steady state. Thereafter, for maintenance therapy, the maximum tolerated dose is administered over a long period of time. When treatment is discontinued, the patient is carefully monitored for any signs of recurrent mood disorders.

  An option for the above-mentioned patients is to add a delta opiate receptor antagonist to naloxone from the first 6 weeks to 3 months after treatment. The naloxone dosage may continue to be increased, or the naloxone dosage may stabilize earlier when combined with a delta antagonist. Non-peptide delta opiate receptor antagonists such as the drugs discussed above, nartrindole, natriben, or one of the drugs described above can be used. Peptide delta antagonists such as ICI-154,129 or ICI-174,864 peptide can also be used. The starting dose for naltrindole is greater than that for naloxone. The starting dose for naltrindole can be as high as 10 mg / kg / dose. Nartrindole may be administered as a transdermal compound or may be administered using other effective dosage forms.

  The main problem is medication for people with serious depression who can be at risk of suicide if the initial dose is too large. In a preferred embodiment of the present invention, patients with clinical depression are at risk of suicide, so such patients are not admitted or are hospitalized to better monitor the patient. Should be treated either in a hospital or in an appropriate facility. These patients are dosed at relatively lower doses at the beginning of treatment, and dose increases occur at a slower rate. Therefore, for depressed patients, treatment should be initiated with a starting dose of 30 mg total, with a loading of only 10 mg of naloxone followed by 10 mg or 20 mg absorbed over 6 hours. Similarly, the dose increase after 2 weeks is more gradual than for the above example. In 2 weeks, an initial dose of 20 mg will be administered followed by 20-40 mg over the next 6 hours. This gradual increase will continue for as many months as necessary to obtain maximum clinical response.

(Dynorphin system)
According to another embodiment of the invention, the neurotransmitter system is a dynorphin system comprising dynorphin as a neurotransmitter. Dynorphins are a class of endorphin compounds that selectively bind to kappa receptors. Dynorphine generally has the opposite effect to endorphins. That is, dynorphin binding to kappa receptors is generally associated with mood deterioration.

  When the neurotransmitter system is the dynorphin system, one type of receptor is a kappa receptor. Kappa receptors are positively associated with undesirable mental, neurological and physiological conditions. Kappa receptors are primarily associated with an unpleasant mood when stimulated. The ligand is a kappa receptor agonist and counteradaptation causes down-regulation of the dynorphin system. Counter-adaptation includes, for example, a decrease in dynorphin biosynthesis or release at the receptor terminus and / or by the pituitary, a decrease in the number of receptors and / or the number of dynorphin binding sites on the receptor, It may be a decrease in the sensitivity of the receptor to binding by a delta receptor agonist and / or dynorphin, or a combination thereof. Counter-adaptation may also up-regulate D2 (dopamine) receptors that are negatively associated with depression.

  In the present invention, various kappa receptor agonists can be used. For example, the kappa receptor agonist is dynorphin [dynorphin [A1-17], H-TYR-GLY-GLY-PHE-LEU-ARG-ARG-ILE8-ARG-PRO-LYS-LEU-LYS-TRP-ASP. -ASN-GLN-OH] and all active peptide fragments and analogs thereof, or peptide-based agonists such as pharmaceutically acceptable salts or carriers thereof. For example, the kappa receptor agonist can be an active C-terminal fragment of dynorphin A (1-8), or a pharmaceutically acceptable salt or carrier thereof.

  The kappa receptor agonist may further be non-peptidic. For example, the kappa receptor agonists include nonbenzomorphan; enadoline; PD117302; CAM569; PD123497; GR89,696; U69,593; TRK-820; trans-3,4-dichloro-N-methyl-N- [1- (1-pyrrolidinyl) cyclohexyl] benzene-acetamide; asimadoline (EMD-61753); benzeneacetamide; thiomorpholine; piperidine; benzo [b] thiophene-4-acetamide; trans-(+/-)-(PD- 117302); 4-benzofuranacetamide (PD-129190); 2,6-methano-3-benzazocin-8-ol (MR-1268); morphinan-3-ol (KT-90); GR-45809; 1-piperazine Carboxylic acid (G -103696); GR-103545; piperzaine; GR-94839; xorphanl; benzeneacetamide (RU-49679); fedotodine; benzeneacetamide (Dup-747); HN-11608; apadrin (RP-60180) Spiradoline mesylate; benzeneacetamide trans-U-50488 methanesulfate; 3FLB; FE200655; FE2000066; analogues of MPCB-GRRI or MPCB-RRI; Can be an opioid; or a pharmaceutically acceptable salt or carrier thereof.

The kappa receptor agonist can be U50,488 (trans-3,4-dichloro-N- [2- (1-pyrrolidinyl) cyclohexyl] benzacetamide and spiradrine (U62,066E). Enadrin and PDl 17302 { (Enadolin [(5R) -5α, 7α, 8β) -N-methyl-N- [7- (1-pyrrolidinyl) -1-oxzspiro [4,5] dec-8-yl] -4-benzofuran Acetamide monohydrochloride], PD117302 [(±) -trans-N-methyl-N- [2- (1-pyrrolidinyl) -cyclohexyl] benzo [b] thiophene-4-acetamido monohydrochloride] and their respective ( +)-Isomers (CAM569 and PD123497) (Perky Davis Research Unit, Kamb Is a highly selective arylacetamide kappa opioid GR89,696 (4-[(3,4-dichlorophenyl) acetyl] -3- (1-pyrrolidinylmethyl) -1-piperazine Carboxylic acid methyl ester fumarate) is a typical arylacetamide developed from the structure of U50,488H, which has a high effect as a K1 agonist U69,593 [((5α, 7α, 8β) )-(+)-N-methyl-N- (7- (1-pyrrolidinyl) -1-oxaspiro (4,5) dec-8-yl) benzeneacetamide] is also a kappa agonist with K1 selectivity. TRK-820 ((-)-17-cyclopropylmethyl-3,14b-dihydroxy-4,5a-epoxy-6b- [N-methyl- Lance-3- (3-furyl) acrylamide] morphinan hydrochloride (Toray, Japan) is a potent kappa agonist with pharmacological properties different from those produced by K1 receptor agonists. Is a benzodiazepine kappa agonist (Sandoz, Inc., Princeton, NJ) U.S. Pat. No. 4,758,562 is also a kappa agonist: trans-3,4-dichloro-N-methyl N- [1- (1-Pyrrolidinyl) cyclohexyl] benzeneacetamide).

  Kappa receptor agonists are disclosed in U.S. Patent Nos. 5,051,428, 5,965,701, 6,146,835, 6,191,126, 6,624,313. No. 6,174,891, No. 6,316,461, No. 6,440,987, No. 4,758,562, No. 6,583,151 ing. Each of these patent documents is incorporated herein by reference.

  The initial dose of the kappa receptor agonist is desirably high enough to induce a counter-adaptive effect, but not high enough to cause a direct effect that is unbearable to the patient. For example, the initial dose of kappa receptor agonist is 0.0005 to 0.05 mg / kg / dose for dynorphin, 5 to 700 mg / dose for enadrine, 1 to 500 μg / dose for FE20665, 0.5 to 100 μg / dose. , 0.01 to 1 mg / kg / dose for U69,593, 0.05 to 5 mg / kg / dose for TRK820, 0.01 to 1 mg / kg / dose for U50488, or 0.01 to 1 mg / kg / dose for PD117302 Can correspond to administration. Desirably, the initial dose of kappa receptor agonist is 0.005-0.02 mg / kg / dose for dynorphin, 100-500 mg / dose for enadrine, 3-100 μg / dose for FE20665, 1-80 μg / dose for FE20666. Administration; 0.1 to 0.7 mg / kg / dose for U69,593, 0.5 to 3 mg / kg / dose for TRK820, 0.5 to 7 mg / kg / dose for U50488, or 0.1 to 0 for PD117302 Equivalent to 7 mg / kg / dose.

  In another embodiment of the invention, the kappa receptor agonist is salvinorin A. Salvinorin A is a neoclerodane diterpene compound that is a very potent hallucinogen that has recently been found to have kappa agonist activity. Salvinorin A is the only known nitrogen-free kappa agonist compound. Salvinorin A is the main active ingredient in the plant S. divinorum (Diviner's sage), a rare species of the family Lamiaceae. Salvia Divinorm has been used for centuries in traditional religious rituals by the Mazatecs native to Oaxaca, Mexico. The initial amount of salvinorin A is desirably 5-50 μg / dose, and the maximum dose is desirably 5000 μg / dose. Salvorin A may be administered transmucosally or desirably as a sustained release formulation over 2-6 hours.

  In certain embodiments of the invention, it may be desirable to administer both a peptidic kappa receptor agonist and a non-peptidic kappa receptor agonist. The two agonists may be administered at about the same time or may be administered sequentially.

  As explained above with respect to other peptidic ligands, the peptidic kappa receptor agonist can be administered, for example, intravenously, transdermally or transmucosally. When it is desirable to use transmucosal administration (to provide high levels of ligand-receptor binding) in conjunction with transdermal administration (to provide extensive ligand-receptor binding) as described above for naloxone There is.

  Since the body develops resistance to anti-opiates about 8 days after the first dose, it may be desirable to increase the dose of the kappa receptor agonist over time. For example, it may be desirable to increase the dosage over a period of 1 to 2 weeks.

  In an example of the method of the invention using salvinorin A, the initial amount of salvinorin A is low to reduce potential side effects. The starting dose is 5 μg to 50 μg. After 2-4 weeks, the dosage is increased by a certain percentage. The amount of increase may be about 5 to 10%, or 50 to 100% or more. In general, twice the initial amount is recommended. Thus, after 2-4 weeks, the patient is administered 20-100 μg of salvinorin A. This dose increase is continued every 2 weeks, 4 weeks, 6 weeks or 8 weeks. Further, the dosage may continue to increase on a quarterly, semiannual, or yearly basis. A dose of 200 μg may cause an increase in unpleasant effects. This occurs by acute administration. By increasing the dosage gradually and chronically, the side effects will be gradually reduced. When the dose is gradually increased gradually, the maximum dose of salvinorin A is 1000 μg to 5000 μg or more.

  In an example of the method of the invention using a dynorphin analog, a rectal suppository (transmucosal) formulation is used. The initial amount is high enough to elicit a counteradaptive response, but low enough to minimize the unpleasant effects of agonist-receptor binding. There are two-part suppositories. The outer layer dissolves rapidly, allowing an initial rapid absorption of the kappa receptor agonist compound. The second layer is gradually degraded to slowly release additional kappa receptor agonist that is gradually absorbed. This results in continuous and sustained release absorption of the peptide kappa receptor agonist compound. It aims to continue a gradual absorption over 6-8 hours so that there is kappa receptor binding during the 6-8 hours when the counter-adaptive response is elicited. This rectal suppository is administered daily (night). After 2-4 weeks, the dose is doubled. This dose is then given over an additional 2-4-6-8 weeks. The dosage is increased intermittently until the onset of side effects prevents further increases. As the dosage is increased, the time interval for increasing the dosage is extended, so that months can elapse before the dosage is increased. In addition, once the high dose is used, the increase is not so dramatic, as it is increased by as much as 5-10%, rather than doubling the dose as initially.

  Enadrin is a non-peptide kappa receptor agonist. Enadrin has drug activity when taken as an oral dose of 1-10 mg / kg. In an example of the method of the invention using enadrine, an initial dose of 100-200 mg is administered daily immediately before the patient goes to bed. After 2-4 weeks, the dosage is increased to 200-500 mg. After a further 2-4 weeks, the dosage is increased to 500-1000 mg. After further 2 weeks, 4 weeks, or 8 weeks or more, the dosage is increased to 1500-2000 mg. The dose is increased unless the side effects become uncontrollable.

  Desirably, the kappa receptor antagonist is not administered during the first period associated with each administration. However, in certain embodiments of the invention, the kappa receptor antagonist is administered during one or more of the second time periods. Exemplary kappa receptor antagonists include the compounds described in US Pat. Nos. 5,025,018, 5,922,887, and 6,284,769. For compounds described in US Pat. No. 5,025,018, suitable dosages include 0.1-10 mg / dose per day, for US Pat. No. 6,284,769, Examples of the dosage include 0.1 to 500 mg / dose.

  The dynorphin neurotransmitter system and its kappa receptor are positively associated with a variety of undesirable mental and neurological conditions. Examples of such conditions include pain, mood disorders, eating disorders, anxiety disorders, craving abnormalities, drug abuse disorders, lack of motivation or ability, pain expected to occur in the future (e.g. future surgery or Due to future physical exercise), chronic pain syndrome, acute pain, fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, shingles, reflex sympathetic dystrophy, neuropathy, inflammatory pain, chronic cancer Pain, major depression, post-traumatic depression, temporary depressed mood, manic depression, mood modulation disorder, generalized mood disorder, annoyance, non-organismal dysfunction, overeating, obesity, anorexia , Bulimia, generalized anxiety, panic disorder, Tourette symptoms, hysteria sleep disorder, respiratory related sleep disorder, loss of motivation due to learning or memory problems, anesthetic, alcohol, nicotine, stimulant, anxiolytic ,During Neuroleptic drugs, drug abuse, such as hallucinogens and marijuana, and physical education, athletic, include lack of motivation or preparation for the desired mental or physical activity, such as learning or test. Down-regulation of the dynorphin system desirably provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions.

(Serotonin series)
According to another embodiment of the invention, the neurotransmitter system is a serotonin system comprising serotonin as a neurotransmitter. Serotonin is a monoamine neurotransmitter. Low serotonin levels are associated with depression. Counter-adaptation causes upregulation of the serotonin system.

  A number of serotonin receptors (at least 14) have been identified. The maximum concentration of serotonin (90%) is located in the gastrointestinal tract. Most of the rest of the body's serotonin is found in platelets and the central nervous system (CNS). The effects of serotonin are noticed in the cardiovascular system, respiratory organs and intestines. Vasoconstriction is a typical response to serotonin.

The function of serotonin is exerted on its interaction with specific receptors. Some serotonin receptor has been cloned _and identified as a _{5HT 1, 5HT 2, 5HT 3} , 5HT 4, 5HT 5, 5HT 6 and 5HT _7. Within the 5HT ₁ group, there are 5HT _1A , 5HT _1B , 5HT _1D , 5HT _1E and 5HT _1F subtypes. There are three 5HT ₂ subtypes, namely 5HT _2A , 5HT _2B and 5HT _2C , and two 5HT ₅ subtypes, namely 5HT _5A and 5HT _5B . Most of these receptors are bound to G proteins that affect the activity of either adenylate cyclase or phospholipase Cg. The 5HT ₃ class of receptors are ion channels.

Some serotonin receptors are presynaptic and others are postsynaptic. The 5HT _2A receptor mediates platelet aggregation and smooth muscle contraction. Mice deficient in this gene become obese due to increased food intake and may cause fatal seizures, so the 5HT ₂ C receptor appears to regulate food intake. The 5HT ₃ receptor is in the gastrointestinal tract and is associated with vomiting. Also in the gastrointestinal tract is 5HT ₄ receptor, which acts on secretion and peristalsis. The 5HT ₆ and 5HT ₇ receptors are distributed throughout the limbic system of the brain, and the 5HT ₆ receptor has a high affinity for antidepressants.

The most common serotonin receptors associated with mood and depression are the first and second serotonin receptors, especially the 5HT _1A receptor.
When serotonin neurons are stimulated and excited, serotonin is released into the synapse. Some serotonin molecules cross the synapse and bind to post-synaptic receptors, which in turn cause excitement of post-synaptic serotonin neurons. Serotonin binds to post-synaptic serotonin neurons, thereby activating the neurons. Such activation results in a series of neural events that are generally associated with good mood.

  When serotonin is released into the synaptic cleft, in fact, only a portion of serotonin binds to the postsynaptic receptor. The majority of serotonin molecules are removed from the synapse by a reuptake mechanism. Some of this serotonin is degraded by monoamine oxidase, an enzyme that degrades both serotonin and norepinephrine.

The third target of the serotonin molecule is the presynaptic autoreceptor. Presynaptic autoreceptors are inhibitory receptors. Presynaptic autoreceptors act in a feedback inhibition loop that functions as a control mechanism for neurotransmitter release. The feedback inhibition loop is a common way for the body to control neuronal activation. Presynaptic autoreceptors, when bound by serotonin or agonists, inhibit further release of serotonin into the synapse. Presynaptic autoreceptors are referred to as 5HT _1A and 5HT _1B presynaptic autoreceptors. The 5HT _1A autoreceptor suppresses the tonic release of serotonin. The 5HT _1B autoreceptor appears to inhibit the induced release and synthesis of serotonin.

When the neurotransmitter system is a serotonin system, one type of receptor can be a serotonin presynaptic autoreceptor such as, for example, the 5HT _1A autoreceptor or the 5HT _1B autoreceptor. In such cases, the ligand is a serotonin presynaptic autoreceptor agonist and the undesired mental, neurological or physiological condition is positively associated with the receptor. Counter-adaptation, for example, increases serotonin biosynthesis and / or release in the synaptic cleft, decreases serotonin reuptake, decreases the number of serotonin presynaptic autoreceptors, serotonin and / or serotonin presynaptic autoreceptor agonists It can be a decrease in the sensitivity of serotonin presynaptic autoreceptors, an increase in the number of serotonin post-synaptic receptors, an increase in the sensitivity of serotonin post-synaptic receptors to serotonin or a serotonin post-synaptic receptor agonist, or a combination thereof.

  Various serotonin presynaptic autoreceptor agonists can be used in the methods of the invention. For example, the serotonin presynaptic autoreceptor agonist may be EMD-68843, basspirone, gepirone, ipsapirone, tandospirone, resopitron, zarospirone, MDL-73005EF, or BP-554.

  The initial dose of a serotonin presynaptic autoreceptor agonist is desirably high enough to elicit a counter-adaptive effect, but not high enough to produce an unbearable direct effect on the patient. For example, the initial dose of serotonin presynaptic autoreceptor agonist is 1 to 400 mg / dose for EMD-68843, 1 to 500 mg / dose for bathpirone, 1 to 500 mg / dose for resopitron, 1 to 500 mg / dose for gepirone, tandospirone Is equivalent to 5 to 500 mg, or zarospirone to 1 to 200 mg. Desirably, the initial dosage of the serotonin presynaptic autoreceptor agonist is 10-100 mg / dose for EMD-68843, 10-100 mg / dose for buspirone, 10-200 mg / dose for resepitro, 10-100 mg / dose for gepirone, It corresponds to 20 to 200 mg for tandospirone or 10 to 100 mg for zalospirone.

Desirably, the serotonin presynaptic autoreceptor antagonist is not administered during the first period associated with each administration. However, in certain embodiments of the invention, the serotonin presynaptic autoreceptor antagonist is administered in one or more of the second time periods. Representative serotonin presynaptic autoreceptor 5HT _1A agonists and antagonists include Elazonan, AR-A2 (AstraZeneca, London, UK); AZD-1134 (AstraZeneca, London, UK); U.S. Patent Nos. 6,462,048, 6,451,803, 6,627,627, 6,602,874, 6,277,852, and 6 , 166, 020. The above patent documents are incorporated herein by reference.

In another embodiment of the present invention, the type of receptor is 5HT ₁ receptor, 5HT ₂ receptor, 5HT ₃ receptor, 5HT ₄ receptor, 5HTs receptor, 5HT ₆ receptor, 5HT ₇ receptor, or Serotonin post-synaptic receptors such as those subtype receptors. The ligand is a serotonin post-synaptic receptor antagonist. Undesirable mental, neurological or physiological conditions are generally negatively associated with these receptors. Counter-adaptation includes increased serotonin biosynthesis and / or release in the synaptic cleft, decreased serotonin reuptake, increased number of serotonin post-synaptic receptors, serotonin and post-synaptic receptors for serotonin and / or post-synaptic receptor agonists It may be increased body sensitivity, decreased number of serotonin presynaptic autoreceptors, decreased sensitivity of serotonin presynaptic autoreceptors to serotonin and / or serotonin presynaptic autoreceptor agonists, or combinations thereof.

  In the method of the present invention, various compounds can be used as serotonin post-synaptic receptor antagonists. For example, the serotonin post-synaptic receptor antagonist may be (S) -WAY-100135, WAY-100635, basspirone, gepirone, ipsapirone, tandospirone, resopitron, zalospirone, MDL-73005EF or BP-554. If desired, the SSRI may be administered simultaneously or sequentially with the aforementioned serotonin modifying agent. This is beneficial because both SSRI therapy and agonist presynaptic counteradaptive therapy result in downregulation of presynaptic receptors. Therefore, the effect of SSRI is amplified by such counter adaptation effect. Second, any down-regulation of post-synaptic serotonin receptors that can occur with SSRI therapy is offset by post-synaptic antagonist counter-adaptive therapy.

  The initial dosage of the serotonin post-synaptic antagonist is desirably high enough to elicit a counter-adaptive effect, but not high enough to produce an unbearable direct effect on the patient. For example, the initial dose of serotonin post-synaptic receptor antagonist corresponds to about 0.01-5 mg / kg / dose for WAY-100635. Desirably, the initial dose of serotonin post-synaptic receptor antagonist corresponds to about 0.025 to 1 mg / kg / dose for WAY-100635.

  A serotonin post-synaptic receptor antagonist may be administered in combination with a serotonin pre-synaptic autoreceptor agonist as described above. Furthermore, counter-adaptation increases the number and / or sensitivity of serotonin post-synaptic receptors when traditional antidepressant drugs that bind at serotonin post-synaptic receptors are administered in combination with serotonin pre-synaptic autoreceptor agonists So the effect can be greatly increased.

  In certain desirable embodiments of the invention, the serotonin post-synaptic antagonist itself is also a serotonin pre-synaptic autoreceptor agonist. It may also be desirable to administer a norepinephrine pre-synaptic alpha-2 adrenoceptor agonist and / or a norepinephrine post-synaptic adrenergic receptor antagonist (described below) in combination with a serotonin post-synaptic antagonist or a serotonin pre-synaptic autoreceptor agonist. .

  Desirably, the serotonin post-synaptic receptor agonist is not administered during the first period associated with each administration. However, in certain embodiments of the invention, the serotonin post-synaptic receptor agonist is administered in one or more of the second time periods. A representative serotonin post-synaptic receptor agonist is BIMT17 (1- [2- [4- (3-trifluoromethylphenyl) piperazin-1-yl] ethyl] benzimidazol- [1H] -2-one). The dosage is 1 to 10 mg / kg (intravenous administration, transdermal administration, subcutaneous administration, etc.). See Borsini, F. et al., Archives of Pharmacology, 352 (3); September 1995: 283-290. Suitable dosage ranges include 1-10 mg / kg / dose (by intravenous, transdermal, or subcutaneous administration) for BIMT17.

  Serotonin post-synaptic receptors are generally negatively associated with various undesirable mental and neurological conditions, and serotonin presynaptic autoreceptors are generally positive for various undesirable mental and neurological conditions. Related. Examples of such conditions include pain, mood disorders, eating disorders, anxiety disorders, obsessive compulsive disorders, appetite disorders, drug abuse disorders, lack of motivation or ability, in the future (eg, future surgery or future Pain expected to occur (by physical exercise) and chronic pain syndrome, acute pain, fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, shingles, reflex sympathetic dystrophy, neurological disease, inflammatory Pain, chronic cancer pain, major depression, post-traumatic depression, temporary depressive mood, manic depression, dysthymic disorder, generalized mood disorder, anxiety, non-organismal dysfunction, overeating Obesity, anorexia, bulimia, generalized anxiety, panic disorder, Tourette symptoms, hysteria sleep disorder, respiratory related sleep disorder, loss of motivation due to learning or memory problems, anesthetic, alcohol, nicotine, stimulant Anti-anxiety drugs, central nervous system depressants, drug abuse, such as hallucinogens and marijuana, and physical education, athletic, include lack of motivation or preparation for the intended spirit or physical activity, such as learning or test. Upregulation of the serotonin system desirably provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions.

(Norepinephrine)
In another embodiment of the invention, the neurotransmitter system is a norepinephrine system comprising norepinephrine as the neurotransmitter and the counteradaptation causes an upregulation of the norepinephine system.

  Norepinephrine is a catecholamine that, along with epinephrine, acts as a neurotransmitter in the central nervous system. There are two types of adrenergic receptors, alpha and beta. In addition, there are at least 10 different subtypes of adrenergic receptors. Norepinephrine is generally more potent at sites where sympathetic neurotransmission is excitable and mediated by alpha receptors. There are two main subclasses of alpha receptors, alpha 1 and alpha 2.

  Norepinephrine behaves like a neuromodulator in the central nervous system. In the absence of other inputs, the central nervous system effects of NE are most prominent when modulating excitatory or inhibitory inputs rather than their effect on the activity of the postsynaptic target. Norepinephrine transmission and regulation is similar to that for serotonin. There is a reuptake mechanism that removes the majority of norepinephrine after release of norepinephrine into the noradrenergic synapse. What are known as alpha-2 adrenergic receptors are presynaptic inhibitory autoreceptors.

  When the neurotransmitter system is the norepinephrine system, one type of receptor can be, for example, a norepinephrine presynaptic alpha-2 adrenergic receptor. In such cases, the ligand is a norepinephrine presynaptic alpha-2 adrenergic receptor agonist. Undesirable mental, neurological or physiological conditions are generally positively associated with the receptor. Counter-adaptation may include increased norepinephrine biosynthesis and / or release in the synaptic cleft, reduced norepinephrine reuptake, reduced number of norepinephrine presynaptic alpha-2 adrenergic receptors, norepinephrine and / or norepinephrine presynaptic alpha-2 adrenaline. Decreased sensitivity of norepinephrine presynaptic alpha-2 adrenergic receptors to receptor agonists, increased number of norepinephrine post-synaptic adrenergic receptors, norepinephrine and / or norepinephrine post-synaptic adrenoceptor adrenoceptor sensitivity of norepinephrine post-synaptic adrenergic receptors It can be an increase, or a combination thereof.

  A variety of compounds can be used as norepinephrine presynaptic alpha-2 adrenergic receptor agonists in the methods of the invention. For example, the norepinephrine presynaptic alpha-2 adrenergic receptor agonist can be clonidine, guanfacine, lofexidine, detomidine, dexamedetomidine, mibazelol, or alpha-methylnoradreniline.

  The initial dose of norepinephrine presynaptic alpha-2 adrenergic receptor agonist is desirably high enough to induce a counteradaptive effect, but not high enough to produce an unbearable direct effect on the patient. For example, the initial dosage is 0.1-10 μg / kg / dose for clonidine, 0.01-10 mg / dose for guanfacine, 0.01-1 mg / dose for lofexidine, 1-100 μg / kg / dose for detomidine, It may correspond to 0.05 to 5 μg / kg dose for medetomidine, 0.05 to 10 μg / kg / dose for mibazelol, or 5 to 500 ng / kg / dose for alpha-methyl noradrenaline. Desirably, the initial dosage is 0.1-0.5 mg / dose for clonidine, 0.1-5 mg / dose for guanfacine, 0.05-0.5 mg / dose for lofexidine, 10-80 μg / kg / dose for detomidine. Administration may correspond to 0.1 to 3 μg / kg / dose for dexamedetomidine, 0.5 to 5 μg / kg / dose for mibazelol, or 10 to 100 ng / kg / dose for alpha-methyl noradrenaline.

  Desirably, the norepinephrine presynaptic alpha-2 adrenergic receptor antagonist is not administered during the first period associated with each administration. However, in certain embodiments of the invention, the norepinephrine presynaptic alpha-2 adrenergic receptor antagonist is administered in one or more of the second time periods. Suitable and non-limiting examples of pre-synaptic and post-synaptic A2AR antagonists include mirtazapine.

  According to another embodiment of the invention, one type of receptor is a norepinephrine post-synaptic adrenergic receptor, such as an alpha receptor, a beta receptor, or a subtype of the receptor. In such cases, the ligand is a norepinephrine post-synaptic adrenergic receptor antagonist. Undesirable mental, neurological or physiological conditions are generally negatively associated with norepinephrine post-synaptic adrenergic receptors. Counter-adaptations include increased norepinephrine biosynthesis or release in the synaptic cleft, decreased norepinephrine reuptake, increased norepinephrine post-synaptic adrenergic receptors, norepinephrine and / or norepinephrine post-synaptic adrenergic receptor agonists. Increased sensitivity of the receptor, decreased number of norepinephrine presynaptic alpha-2 adrenergic receptors, reduced sensitivity of norepinephrine presynaptic alpha-2 adrenergic receptors to norepinephrine and / or norepinephrine presynaptic alpha-2 adrenergic receptors agonists, Or a combination thereof.

  In the method of the present invention, various compounds can be used as norepinephrine post-synaptic adrenergic receptor antagonists. For example, the norepinephrine post-synaptic adrenergic receptor antagonist can be idazoxan, SKF104080 or SKF104856. The initial dose of norepinephrine post-synaptic adrenergic receptor antagonist is desirably high enough to elicit a counteradaptive effect, but not high enough to produce an unbearable direct effect on the patient. For example, the initial dose may correspond to 0.5-100 mg / dose for idazoxan. Desirably, the initial dosage may correspond to 5-50 mg / dose for idazoxan.

  Desirably, norepinephrine post-synaptic adrenergic receptor agonists are not administered during the first period associated with each administration. However, in certain embodiments of the invention, the norepinephrine post-synaptic adrenergic receptor agonist is administered in one or more of the second time periods.

  A norepinephrine post-synaptic adrenergic receptor antagonist may be administered in combination with a norepinephrine pre-synaptic alpha-2 adrenergic receptor agonist as described above. Further, when conventional antidepressant drugs that bind at the norepinephrine post-synaptic adrenergic receptor are administered in combination with a norepinephrine pre-synaptic alpha-2 adrenergic receptor agonist, the number of norepinephrine post-synaptic adrenergic receptors and / or As sensitivity increases, the effect can be greatly increased.

  In certain desirable embodiments of the invention, the norepinephrine post-synaptic adrenergic receptor antagonist itself is also a norepinephrine pre-synaptic alpha-2 adrenergic receptor agonist. Administering a serotonin post-synaptic antagonist and / or a serotonin pre-synaptic autoreceptor agonist (as described above) in combination with a norepinephrine pre-synaptic alpha-2 adrenoceptor agonist or a norepinephrine post-synaptic adrenergic receptor antagonist Sometimes desirable.

Norepinephrine post-synaptic adrenergic receptors are generally negatively associated with various undesirable mental and neurological conditions, while norepinephrine presynaptic alpha-2 adrenergic receptors are associated with various undesirable mental conditions and Positively associated with neurological condition. Examples of such conditions include pain, mood disorders, eating disorders, anxiety disorders, obsessive compulsive disorders, craving disorders, drug abuse disorders, lack of motivation or ability, which may be in the future (eg future surgery or future Expected to occur) and chronic pain syndrome, acute pain, fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, shingles, reflex sympathetic dystrophy, neurological disease, inflammation Pain, chronic cancer pain, major depression, post-traumatic depression, temporary depressed mood, manic depression, dysthymic disorder, generalized mood disorder, anxiety, non-organismal dysfunction, Overeating, obesity, anorexia, bulimia, generalized anxiety, panic disorder, Tourette symptoms, hysteria sleep disorder, respiratory related sleep disorder, loss of motivation due to learning or memory problems, anesthetic, alcohol, nicotine, sensation There agents, anti-anxiety drugs, central nervous system depressants, drug abuse, such as hallucinogens and marijuana, and physical education, athletic, include lack of motivation or preparation for the mental or physical activity desirable, such as learning or test. Upregulation of the norepinephrine system desirably provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions.
(CRF system)
The hypothalamus-pituitary-adrenal (HPA) axis is the regulatory mechanism that makes the body respond to stress. The hypothalamus is the general control center for many body hormones. In response to stress, the pituitary gland releases corticotropin-releasing factor (CRF, also known as corticotropin-releasing hormone), which reaches the anterior pituitary gland, and hormones ACTH (adrenocorticotropic hormone) and β-endorphin Induces a change that is released into the circulation. ACTH reaches the adrenal gland adjacent to the kidney and stimulates the release of cortisol. When cortisol is released into the circulation, it initiates a series of metabolic effects that reduce the adverse effects of stress. There is also negative feedback to both the hypothalamus and the anterior pituitary, blocking further cortisol release.

  In addition to CRF emission from the hypothalamus, CRF is present in many other areas of the cortex. When released from the hypothalamus, it acts as a hormone. In the cortex, CRF molecules act as neurotransmitters. The neurotransmitter action of CRF results in some behavioral effects common to depression. Some of these effects are due to CRF effects on other neurotransmitter systems, such as the serotonin and norepinephrine (NE) systems. Thus, the relevance of CRF to depression is very complex and is related not only to effects on the HPA axis, but also to direct effects on the brain and other neurotransmitter systems.

  CRF is a 41 amino acid peptide. It was first isolated and sequenced by Vale in 1981 (Vale W, Spirits J, River C, River J (1981): Charactorization of acetoid stenp tide tide tide tide tide tide tide tide tide tide tide tide tide tide tide tide tide tide tide tide sept. 213: 1394-1397). The sequence of CRF has been determined in various species such as sheep, human, rat, pig, goat and cow. In all species, CRF is a 41 amino acid residue single chain polypeptide. Rat and human CRF are identical to each other and differ in 7 amino acid residues from sheep CRF. All three CRFs have close amino acid identity, Sabagin, a 40 amino acid peptide present in frog skin, and urotensin I, a 41 amino acid peptide derived from fish tail pituitary, and several biology Common characteristics. Goat and sheep CRF are identical but differ by one amino acid from bovine CRF. Porcine CRF is more closely similar to rat / human CRF. Since CRF and related peptides are amidated at the carboxy terminus and the COOH terminal free acid of CRF is less than 0.1% of the ability of the native CRF, the importance of amidation to the biological activity of the peptide Is suggested. A study to determine the solution structure of CRF using proton nuclear magnetic resonance spectroscopy suggested that human CRF contains a long N-terminal tetrapeptide that binds to a defined α-helix at residues 6-36. . Since α-helix oCRF (9-41) is an antagonist of CRF, the need for α-helix conformation is emphasized for receptor binding and biological activity. (Errol B. De Souza and Dimitri E. Grigoriadis, Corticotropin-Releasing Factor: Physiology, Pharmacology and Role in Central Nervous System and Immune Disorders, Psychopharmacology-Fourth Generation of Progress, 2000, http://www.acnp.org/g4 /GN40100049/CH049.html).

  Mood, mood disorders and related conditions arise from a complex chain of central nervous system events that correlate with many neurotransmitter systems. The most common mood disorder is depression. Depression is a clinical diagnosis with numerous physical and psychological symptoms and is caused by numerous neurotransmission system changes. Other systems related to depression other than the CRF system include norepinephrine, serotonin, substance P, dynorphin (κ-receptor) and endogenous endorphins (mu and / or delta opiate receptors). In addition, these neurotransmitter systems are associated with many other adverse mental and neurological conditions, such as bipolar disorder, obsessive-compulsive disorder, anxiety, phobias, stress disorders, drug abuse, sexual disorders, eating disorders , Motivation disorders, and pain disorders.

  Stress appears to be a major cause of adult depression and anxiety. Whether a patient is actually clinically repressed also depends on the genetic predisposition of depression and any major early life stress state (Lott, Psychiatrin Times 1999 Oct; Vol. XVI, Issue 10).

  The HPA axis plays an important role in depression and anxiety due to its role in stress conditions. It has been determined that CRF levels are increasing in depression (ie, melancholic depression, not atypical depression—see below). Cortisol levels are also generally increased in depression. This is due to the increased activity of the HPA axis, most likely due to a negative inhibition loop failure. In other words, the sustained release and increase of CRF in the circulation, which may be the result of a chronic stress state, occurs in normal non-depressed patients and is therefore not inhibited by elevated cortisol levels.

  Depression studies generally classify all patients into one category. However, depression has different forms and tends to have different regulatory changes to the HPA axis. There are two notable subtypes of depression: melancholic and atypical. A melancholic depression is the most common form. The melancholic patients are generally anxious, future anxiety, loss of responsiveness to the environment, insomnia, lack of appetite (weight loss), daytime fluctuations, and morning depression. Atypical patients are generally the opposite in these areas. Atypical patients are generally lethargic and tired, over-appetite (weight gain), oversleep, responsive to the environment, show various depression during the day, and are best in the morning . (Gold et al, “Organization of the stress system and it's desregulation in melanholic and atypical depression: high vs. low CRH / NE states.

Melancholic patients are characterized by hyperactivity of the central CRH system and hyperactivity of the HPA axis. On the other hand, atypical depression is characterized by a decrease in activity of the central CRF system and inactivity of the HPA axis. (Kasckow, JW et al, “Coricotropin-releasing home in depression and post-traumatic stress disorder.” Peptides, 2001 May; 22 (5): 845-51. I think that the. It may be related to worsening negative feedback adjustment of the HPA axis. (Levitan RD, “Low-dose dexamethasone challenge in women with atypical majpr depression: pilot study.” J Psych Neurosci, 2002 Jan .: 4751);
Post-traumatic stress disorder (PTSD) is the third category and it is also unique. PTSD is characterized by a hyperactive central CRH system, similar to melancholic depression, but, like atypical depression, the HPA axis is underactive. (Levitan, 2002)
Anxiety differs from melancholic depression in the pattern of HPA axis changes. Depression is characterized by hypercortisolemia, non-suppression after dexamethasone and a decrease in the number of glucocorticoid receptors. Anxiety is characterized by hypocortisolemia, hyperinhibition after dexamethasone and an increase in the number of glucocorticoid receptors. (Boyer, P, “Do Anxiety and depression have a common pathological mechanical?” Acta Psychiatra Scan Suppl 2000; (406): 24-9)
Eating disorders are highly related to mood and / or stress. Dallan et al. (Chronic stress and obesity: a new view of “comfort food”. Proc Natl Acad Sci USA 2003 Sep 30; 100 (20): 11696-701 is generally less responsive to weight in rats. However, human chronic stress has demonstrated that comfortable dietary intake increases and gains weight, or that food consumption decreases and weight decreases. As discussed above, melancholic depression tends to be associated with decreased appetite and weight, and atypical depression tends to be associated with increased diet and weight gain.

Conventional strategies to deal with conditions associated with neurotransmitters are focused on improving abnormally high or low levels of synaptic neurotransmission. Conventional therapeutic agents have the function of directly regulating the action of the neurotransmitter system. Such agents may be anxiolytics, hypnotics, or selective reuptake inhibitors, such as benzodiazepines (eg, diazepam, lorazepam, alprazolam, temazepam, flurazepam, and chlorodiazepoxide), TCA, MAOI, SSRI (eg, fluoxetine, hydrochloride), NRI, SNRI, serotonin presynaptic autoreceptor antagonist, 5HT ₁ agonist, GABA-A modulator, serotonin 5HT _2C and / or 5HT _2B modulator, β-3 adreno Sceptor agonists, NMDA antagonists, V1B antagonists, GPCR modulators, dynorphin antagonists, and substance P agonists. CRF antagonists are considered a new class of antidepressants (Nielsen, Life Sci, 2006, Jan 25; 78 (9): 909-19).

  For the CRF system, the response to the drug is expected to vary depending on the type of depression or anxiety being treated because the HPA axis varies differently with different types of depression. In fact, an antidepressant that is effective in reducing CRH production, ie TCA, has good efficacy for melancholic depression. This drug is not particularly effective in the treatment of atypical depression that does not relate to activation of the CRH production system, but rather reduces the secretion of CRH (Licinio, J, et al, “Role of corticotrophin releasing home 41). in depressive illness. "Bailliers Clin Endocrinol Metab, 1991 Mar; 5 (1): 51-8).

  Numerous studies have shown the potential of CRF antagonists as antidepressants (O'brien, Hum Psychopharmacol, 2001, Jan; 16 (1): 81-87 and Arborelius, et al, J Endocrinol 1999, 160. : 1-12). Because they block the effects of hyperactive CRF systems, CRF antagonists are indicated for conditions with hyperactive CRF systems, such as melancholic depression rather than atypical depression with hypoactive CRF systems Seem.

  β-endorphin is an endogenous opiate compound that is advantageous during stress responses. It reduces the pain sensation. Endorphins are the product of an evolutionary mechanism that ensures survival first and later recovery. Pain usually results in behaviors that damage survival changes. For example, if an animal is attacked, stops licking the wound, and instead escapes the attacker, the animal's life is compromised. But fear triggers the release of endorphins, impeding pain perception. In addition, endorphins have an impact on the immune system, better assist in the protection of infection, and are advantageous when animals are injured.

  β-endorphin is closely related to HPA. In addition to improving effects on areas of the brain cortex, such as pain response, β-endorphin also regulates CRF release through negative inhibition in the hypothalamus (Figure X).

  β-endorphin and endogenous opioid peptides generally inhibit HPA by reducing the release of CRF (Burnett, J Affective Disord 1999 Jun; 53 (3): 263-8). This latter study showed that the depressed opioid tone was reduced in depressed patients. In other words, there is down-regulation of the β-endorphin system in depressed patients. This is confirmed by another study demonstrating that depression is associated with decreased circulating levels of β-endorphin (Cohen, AMJ Psychiatry 1984; 141: 629-32., And Djurovic, Farmaco 1999 Mar 31; 54 ( 3): 130-3).

  It has also been demonstrated that β-endorphin is increased in patients with depression (Goodwin, J Affection Dissole 1993 Dec; 29 (4): 281-9). This finding appears to be inconsistent with the above study where depression and endorphin levels were reduced, but the latter study is actually consistent with the above study. This is explained as follows. In the latter study (Goodwin), β-endorphin is indeed negatively associated with the severity of depressive symptoms, so the fact that β-endorphin down-regulation is associated with depression, and the above study (Cohen & Djurvec) Is consistent with Goodwin's study demonstrated that acute psychosocial precipitators can increase β-endorphin levels in the acute phase. This indicates that acute stressful events can trigger such an increase in CRF, thus overturning the down-regulated β-endorphin system. However, in Goodwin's study, as demonstrated in the Cohen and Djurovic studies, there is a common β-endorphin down-regulation in depression, and the severity of depression and the inverse level of β-endorphin are inversely correlated. The fact of doing was also confirmed. In summary, β-endorphin may be elevated in the acute phase in depressed patients undergoing stressful lowering events, but in terms of daily steady state levels, depressed patients have lower circulating dolphin than normal levels.

  The Burnett (1999) study summarizes that some clinically depressed patients can self-administer opiates. In those conditions, the opiate replaces “lost” or down-regulated endogenous endorphins. These self-medication opiates play the same role as endogenous endorphins, ie reduce CRF release by inhibiting HPA.

  HPA hyperactivity is related to depression, but in recent years, CRF antagonists have been used to treat depression. There are certain limitations to using CRF antagonists for the treatment of depression.

  Thus, in one embodiment of the invention, the neurotransmitter system is a CRF system comprising corticotropin releasing factor as a neurotransmitter, the receptor type is a CRF receptor, the ligand is a CRF receptor agonist, Causes down-regulation of the CRF system. Regulation of the CRF system by counter adaptation is described in US Provisional Patent Application No. 60 / 777,190, entitled “METHOD OF REGULATING THE CRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS” filed on Feb. 27, 2006.

The CRF receptor may be, for example, CRF-1 or CRF-2. CRF-1 is generally associated with mood, while CRF-2 is generally associated with memory.
CRF agonists affect both HPA and the hypothalamic system. With respect to HPA, CRF agonists release ACTH and β-endorphin into the circulation. Since β-endorphin is known to ameliorate hyperactive CRF conditions such as depression and anxiety, release of β-endorphin is advantageous in the short-term setting (ie, the first phase for each administration). However, CRF agonists also increase ACTF release and affect increased cortisol release in the short term. If the goal is to suppress the activity of the hyperactive CRF system, an increase in cortisol is not necessary. In addition, the agonist acts directly on the extrahypothalamic CRF system. In summary, short term hyperactive CRF status is exacerbated by effects on ACTH release and effects on the extrahypothalamic CRF and AVP system. However, according to the present invention, the methods described herein induce counter-adaptation and overall down-regulation of the CRF system, eg, through ACTH release and down-regulation of the extrathalamic CRF system.

  Counter-adaptation is a reduction in the biosynthesis or release of corticotropin releasing factor by the hypothalamus, a decrease in the number of CRF receptors and / or CRF receptor binding sites, receptors for binding by CRF receptor agonists and / or corticotropin releasing factors May be reduced in sensitivity, or a combination thereof.

  A variety of compounds can be used as CRF receptor agonists. For example, many peptide-based compounds are CRF receptor agonists. Examples include analogs of corticotrophin releasing factor, and pharmaceutically acceptable salts and derivatives thereof. Cortagine is a CRF receptor agonist suitable for use in the methods of the present invention, each of which is incorporated herein by reference, Tezval, et al, PNAC, 101 (25) (2004) and Todorovic, C.I. , Et al. , Neurosci Bobehav Rev. , 2005, 29 (8): 1323-1333. Examples of CRF receptor agonists are further described in US Pat. Nos. 5,132,111; 5,278,146; 5,824,771, each incorporated herein by reference. No. 5,844,074; No. 6,214,797; No. 6,670,371; No. 6,812,210; No. 6,953,838.

  The initial dose of CRF receptor agonist is desirably high enough to induce a counter-adaptive effect, but not high enough to produce a direct effect that is unbearable to the patient. For example, the initial dosage may be about 0.1 to 100 μg / kg / day as the initial amount and 100 to 1000 μg / kg / day with sustained release for 8 hours. In certain embodiments of the invention, the initial dose of CRF receptor agonist may be about 1-50 μg / kg / day as an initial amount and 20-50 μg / kg / day with 8 hours sustained release. .

  Desirably, neither a CRF receptor antagonist nor an AVP receptor antagonist is administered during the first period for each administration of a CRF receptor agonist. However, in certain embodiments of the invention, the CRF receptor antagonist and / or AVP receptor antagonist is administered one or more times during a second period associated with each administration of the CRF receptor agonist.

  Examples of CRF antagonists include R121919 (Zobel, J Paychiatr Res 2000 May-June; 34 (3): 171-81), DMP696 (Maciag, Neuropsychopharmacol 2002; 26: 574-582), Antalarmin (WilMl bilmol s bilmol bilMil bilmol smol bilmol Mar; 5 (2): 137-41), CP-154,526 (Mansbach, Eur J Pharmacol 1997 Mar 26; 323 (1): 21-6), SSR125543A (Briebel, J Pharmacol Exp Ther 2002 (Apr; 1) 333-45), 2-arylamino-4-trifluoromethylaminomethyl Triazole antagonists (Dubowchik, Bioorg Med Chem Lett 2004 Nov 17; 13 (22); 3997-4000), and astresin (Spine, Neuropsychopharmacol 2000; 22: 230-239), and their pharmaceutically acceptable salts, analogs And derivatives.

Examples of AVP receptor antagonists, d (CH2) 5Tyr (Me ) AVP, Phaa-d-TYr (Me) -Phe-Gln-Asp-Pro-Arg-Tyr-NH 2, [Lys (3N 3, Phpa ⁸ ] HO-LVA, [d (CH2) 5, D-Ile2, Ile4] -AVP, [125I] -d (CH2) 5 [D-Tyr (Et) 2, Val4, Tyr-NH29] AVP, etc. As well as any analog of an AVP peptide having AVP antagonist activity (Cys-Tyr-Phe-Gln-Asp-Cys-Pro-Arg-Gly). AVP peptide antagonists may further include propeptide molecules that are cleaved enzymatically to active AVP antagonists. Examples of AVP receptor antagonists include OPC-21268 (1- (1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidyl) -3,4-dihydro-2 (1H) -quinolinone), R49059 (V1a antagonist), OPC-31260 (5-dimethylamino-1- [4- (2-methylbenzoylamino] benzoyl) -2,3,4,5-tetrahydro-1H-benzazepine), conivaptan (YM087- VIa and V2 antagonists), Vaprisol (conivaptan) (V1a and V2 antagonists), VPA985 (V2 antagonist), and YM471 [(Z) -4 '-[4,4-difluoro-5- [2- (4 -Dimethylaminopiperidino] -2-oxoethylidene ] -2,3,4,5-tetrahydro-1H-1-benzazepine-1-carbonyl] -2-phenylbenzanilide monohydrochloride). AVP receptor antagonists are also described in US Pat. Nos. 6,627,649 and 6,495,542, each incorporated herein by reference.

  In another embodiment of the invention, the mu and / or delta opiate receptor antagonist is used in combination with a CRF agonist in the first phase, such that the ratio of the dose half-life to the interval between doses is ½ or less. Administered. The method of administering the mu and / or delta opiate receptor antagonist is as described earlier in this specification. This is due to the fact that the use of CRF agonists is intended to cause down-regulation of the CRF system, but may also have the unwilling consequence of down-regulating β-endorphin release from the anterior pituitary gland. It may be desirable. Such a decrease in endorphin release elicits an adverse effect for those undesirable conditions that are inversely correlated with circulating endorphin levels, such as those required for improvement such as depression and anxiety. Repeated administration of opiate antagonists can have two important effects: inhibiting endorphin down-regulation by CRF agonists and inducing the above-mentioned upregulation of the endorphin system. The principle of administration of opiate antagonists to induce up-regulation of the endogenous endorphin system is as described earlier in this specification. As described above, it may be desirable to administer the CRF and / or AVP antagonist in a second period associated with each administration of the CRF agonist. Desirably, neither the CRF receptor antagonist nor the AVP receptor antagonist is administered during the first period associated with each administration.

  CRF agonist administration according to this embodiment of the invention may be utilized to treat undesirable mental, neurological or physiological conditions positively associated with CRF receptors. Examples of undesirable mental, neurological or physiological conditions that are positively associated with CRF receptors and can be treated using this method include melancholic depression, lack of memory, Necessity of memory improvement expected to occur, anxiety and anxiety related disorders, anorexia and hypoeating disorders such as anorexia and bulimia, stress, stress expected to occur in the future, post-traumatic stress Disability and lack of motivation due to learning or memory problems. In desirable embodiments of the present invention, down-regulation of the CRF system provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions positively associated with CRF receptors.

  Intermittent administration of CRF receptor agonists (with or without intermittent administration of mu and / or delta opiate receptor antagonists) improves the patient's ability to treat stress conditions if the stress condition should occur in the future It will be advantageous to do. This is explained by the fact that a small amount of intermittent stress is actually good for living organisms. Such a small amount of intermittent stress stimulates proper adaptability, so that organisms can better treat future stress conditions. Intermittent stress actually increases cortisol levels intermittently. Such intermittent increases in cortisol levels also occur with intermittent administration of CRF and / or AVP agonists. In other words, intermittent administration of a CRF receptor agonist mimics that caused by a small amount of intermittent stress. It induces patient physiological stress (ie increased CRF release) on a short-term basis and is small enough for stress and short enough for duration, so chronic chronic stress (ie hyperactive CRF and / or AVP) System side) is not caused. The method is to better treat the greater stress that will occur in the future. In other words, surviving organisms that undergo a small amount of intermittent stress (ie, a temporary increase in CRF levels) will continue to do so in the future compared to organisms that have not received such short-term temporary stress. It can be better dealt with by the great stress (ie, a large increase in CRF levels) when If an acute stress condition occurs, it may be desirable to administer the CRF receptor antagonist and / or the AVP receptor antagonist in the second period associated with each administration.

  In another embodiment of the present invention, the neurotransmitter system is a CRF system comprising corticotropin releasing factor as a neurotransmitter, the receptor type is a CRF receptor, the ligand is a CRF receptor antagonist, Causes upregulation of the CRF system. Regulation of the CRF system by counter adaptation is described in US Provisional Patent Application No. 60 / 777,190, entitled “METHOD OF REGULATING THE CRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS” filed on Feb. 27, 2006.

The CRF receptor may be, for example, CRF-1 or CRF-2. CRF-1 is generally associated with mood, while CRF-2 is generally associated with memory.
Counter-adaptations include increased biosynthesis or release of corticotropin releasing factor by the hypothalamus, increased number of CRF receptors and / or CRF receptor binding sites, receptors for binding by CRF receptor agonists and / or corticotropin releasing factors May be increased sensitivity, or a combination thereof.

  Suitable CRF antagonists are described earlier in this specification. The initial dose of CRF receptor antagonist is desirably high enough to induce a counter-adaptive effect, but not high enough to produce a direct effect that is unbearable to the patient. For example, the initial dosage may be about 0.1 to 100 μg / kg / day as the initial amount and 100 to 1000 μg / kg / day with sustained release for 8 hours. In certain embodiments of the invention, the initial dose of CRF receptor antagonist may be about 1-50 μg / kg / day as an initial amount and 20-50 μg / kg / day with 8 hours sustained release. .

  Desirably, neither the CRF receptor agonist nor the AVP receptor agonist is administered during the first period associated with each administration of the CRF receptor agonist. However, in certain embodiments of the invention, the CRF receptor agonist and / or AVP receptor agonist is administered one or more of the second time periods associated with each administration of the CRF receptor antagonist. Suitable CRF receptor agonists and AVP receptor agonists are described earlier in this specification.

  In another embodiment of the invention, the mu and / or delta opiate receptor antagonist is combined with the CRF antagonist in the first period such that the ratio of dosing half-life to inter-dosing period is ½ or less. Be administered. Methods for administering mu and / or delta opiate receptor antagonists and their benefits are as described earlier in this specification.

Administration of CRF antagonists according to these embodiments of the invention may be utilized to treat an undesired mental, neurological or physiological condition in a patient that is negatively associated with the CRF receptor. Examples of undesirable mental, neurological or physiological conditions that are negatively associated with CRF receptors and can be treated using this method include, for example, atypical depression, weight gain and binge eating disorder, Examples include fatigue and fatigue. In desirable embodiments of the invention, up-regulation of the CRF system provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions negatively associated with CRF receptors.
(AVP system)
AVP is a hormone also called ADH (antidiuretic hormone) and is a nonapeptide (Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly) with a cyclic structure between two cysteine residues. A cyclic structure is formed through disulfide bridges. AVP is a 164 amino acid long active hormone, initially synthesized as peptide ppAVP. The biologically active moiety is AVP (20-28). AVP nonapeptides are further broken down into smaller biologically active fragments, namely AVP (4-9), AVP (4-8), AVP (5-9), AVP (5-8), in certain examples. These small fragments lack peripheral endocrine activity, but have demonstrated selective activity within the CNS.

  AVP hormones are produced in the hypothalamus as well as CRF (and other release factors). However, AVP is produced from a secretor that is different from those that produce release factors such as CRF (which flows directly to the anterior pituitary gland). The posterior pituitary gland is effectively an extension of the hypothalamus. AVP producing cell bodies are present in the hypothalamus. AVP is transported from the cell body to the axon ends of these neuronal cell bodies located in the posterior pituitary gland. AVP is released into the circulation from the posterior pituitary gland.

  AVP in the environment has two basic actions, peripheral and central. Peripheral effects are associated with vasoconstriction, glycogen metabolism and antidiuresis. Central effects are related to learning and memory, social behavior, thermoregulation, autonomic function and mood.

  AVP works in concert with CRF to stimulate ACTH release from the anterior pituitary gland. AVP also has a direct renal effect on cortisol release. AVP has a similar effect to CRF on β-endorphin and stimulates β-endorphin release from the anterior pituitary gland.

  AVP plays a role in stress, ie depression and anxiety. Just as certain mood disorders (ie, depression and anxiety) are associated with the hyperactive CRF system, depression and anxiety are also associated with the hyperactive AVP system. AVP antagonists acting at the V1b receptor have demonstrated early favorable results as potential antidepressants and anxiolytics in animal studies. In addition, antagonists that act at the Vla receptor may also play a role as antidepressants and anxiolytics.

  Therefore, in one embodiment of the present invention, the neurotransmitter system is an AVP system comprising corticotropin releasing factor as a neurotransmitter, the receptor type is an AVP receptor, the ligand is an AVP receptor agonist, Causes down regulation of the AVP system. Regulation of the AVP system by counter adaptation is described in US Provisional Patent Application No. 60 / 777,190 entitled “METHOD OF REGULATING THE CRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS” filed on Feb. 27, 2006.

  The AVP receptor may be, for example, V1R (also known as V1a), V2R or V3R (also known as V1b). V3R is the main receptor of the pituitary gland. V1R is mainly present in the liver and brain, and V2R is mainly present in the kidney. In desirable embodiments of the invention, the AVP receptor is a VIR receptor or a V3R receptor.

  Counter-adaptation is a reduction in the biosynthesis or release of arginine vasopressin by the hypothalamus, a decrease in the number of AVP receptors and / or the binding sites of AVP receptors, the sensitivity of the receptors to binding by AVP receptor agonists and / or arginine vasopressin. May be reduced, or a combination thereof.

  A variety of compounds can be used as AVP receptor agonists. For example, many peptide compounds are AVP receptor agonists. The peptide may be synthetic or may be from a mammalian source, such as bovine or pig, or others. The peptide may be linear or cyclic. Suitable peptide AVP agonists include, for example, ferripressin (2-L-Phe-8-L-Lys AVP), desmopressin (1- (30-mercaptopropionic acid) -8-D-AVP), and AVP agonist activity. Peptide analogs of any of the AVP peptides (Cys-Tyr-Phe-Gln-Asn-Cys-Pro-Arg-Gly) are included. AVP peptide agonists may further include propeptide molecules that are cleaved enzymatically to active AVP agonists. An AVP peptide agonist may further be any compound that contains a smaller biologically active fragment of the AVP nonapeptide, such as AVP (4-9), AVP (4-8), AVP (5-9), AVP (5-8). May be included. Other AVP receptor agonists suitable for use in the present invention include US Pat. Nos. 6,090,803; 6,096,735, each incorporated herein by reference. 6,096,736; 6,194,407; 6,235,900; 6,268,360; 6,297,234; 6,335,327 No. 6,344,451; No. 6,620,807; No. 6,642,223; and No. 6,831,079. As will be appreciated by those skilled in the art, pharmaceutically acceptable salts or derivatives of the above AVP agonists can also be used in the methods of the invention.

  The initial dose of the AVP receptor agonist is desirably high enough to elicit a counter-adaptive effect, but not high enough to produce a patient-tolerable direct effect. For example, the initial dosage may be about 0.1 to 100 μg / kg / day as the initial amount and 100 to 1000 μg / kg / day with sustained release for 8 hours. In certain embodiments of the invention, the initial dose of AVP receptor agonist may be about 1-50 μg / kg / day as the initial amount and 20-50 μg / kg / day with 8 hours sustained release. .

  Desirably, neither the CRF receptor antagonist nor the AVP receptor antagonist is administered during the first period associated with each administration of the CRF receptor agonist. However, in certain embodiments of the invention, the CRF receptor antagonist and / or the AVP receptor antagonist are administered in one or more of the second phases associated with each administration of the CRF receptor agonist. CRF receptor antagonists and AVP receptor antagonists are described earlier in this specification.

  In another embodiment of the present invention, the mu and / or delta opiate receptor antagonist is combined with the AVP agonist in the first period such that the ratio of the administration half-life to the period between administrations is ½ or less. Be administered. Methods of administration of mu and / or delta opiate receptor antagonists are described earlier in this specification. This is desirable due to the fact that the use of AVP agonists is intended to cause down-regulation of the AVP system, but also has the unintended consequence of also down-regulating β-endorphin release from the anterior pituitary gland. There is a case. Such a decrease in endorphin release induces an adverse effect for undesirable conditions that are inversely correlated with circulating endorphin levels, such as those required for amelioration of depression and anxiety. Repeated administration of opiate antagonists can have two important effects: inhibiting endorphin down-regulation by AVP agonists and inducing the upregulation of the endorphin system described above. The principle of administration of opiate antagonists to induce up-regulation of the endogenous endorphin system is described earlier in this specification. As previously described, it may be desirable to administer the CRF and / or AVP antagonist in a second period associated with each administration of the AVP agonist. Desirably, neither the CRF receptor antagonist nor the AVP receptor antagonist is administered during the first period associated with each administration.

  AVP agonist administration according to these embodiments of the present invention may be utilized to treat an undesired mental, neurological or physiological condition in a patient positively associated with the AVP receptor. Examples of undesirable mental, neurological or physiological conditions that are positively associated with the AVP receptor and can be treated using this method include melancholic depression, lack of memory, and future Need for improved memory, anxiety and anxiety related disorders, loss of appetite and decreased eating disorders such as anorexia and bulimia, stress, stress expected to occur in the future, post trauma Stress disorder and lack of motivation due to learning or memory problems. In desirable embodiments of the invention, down-regulation of the AVP system provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions positively associated with AVP receptors.

  Intermittent administration of AVP receptor agonists (with or without intermittent administration of mu and / or delta opiate receptor antagonists) improves the patient's ability to treat stress conditions if stress conditions are to occur in the future It will be advantageous to do. This is explained by the fact that a small amount of intermittent stress is actually good for living organisms. Such a small amount of intermittent stress stimulates proper adaptability, so that the organism can better treat future stress conditions. Intermittent stress actually increases cortisol levels intermittently. Such intermittent increases in cortisol levels also occur with intermittent administration of AVP agonists. In other words, intermittent administration of an AVP receptor agonist mimics that caused by a small amount of intermittent stress. It induces a patient's physiological stress (ie, increased AVP release) on a short-term basis and is small enough for stress and short enough for duration, so chronic chronic stress (ie hyperactive CRF and / or A side effect that can cause (AVP system) does not occur. The method is intended to better treat the greater stress that will occur in the future. In other words, surviving organisms that receive a small amount of intermittent stress (ie, a temporary increase in AVP levels) will continue to do so in comparison to organisms that have not received such short-term temporary stress. Large stresses (i.e., large increases in AVP levels) can be better treated when occurs. If an acute stress condition occurs, it may be desirable to administer the CRF receptor antagonist and / or the AVP receptor antagonist in the second period associated with each administration.

  In another embodiment of the invention, the neurotransmitter system is an AVP system comprising corticotropin releasing factor as a neurotransmitter, the receptor type is an AVP receptor, the ligand is an AVP receptor agonist, Causes upregulation of the AVP system. Regulation of the AVP system by counter adaptation is described in US Provisional Patent Application No. 60 / 777,190 entitled “METHOD OF REGULATING THE CRF AND AVP SYSTEMS BY INDUCING COUNTERADAPTATIONS” filed on Feb. 27, 2006.

  The AVP receptor may be, for example, V1R (also known as V1a), V2R or V3R (also known as V1b). V3R is the main receptor of the pituitary gland. V1R is mainly present in the liver and brain, and V2R is mainly present in the kidney. In desirable embodiments of the invention, the AVP receptor is a VIR receptor or a V3R receptor.

  Counter-adaptations include increased biosynthesis or release of corticotropin releasing factor by the hypothalamus, decreased number of AVP receptors and / or AVP receptor binding sites, binding of receptors for binding by AVP receptor agonists and / or arginine vasopressin. There may be an increase in sensitivity, or a combination thereof.

  Suitable AVP antagonists are described earlier in this specification. The initial dose of an AVP receptor agonist is desirably high enough to induce a counter-adaptive effect, but not high enough to produce a direct effect that is unbearable to the patient. For example, the initial dosage may be about 0.1 to 100 μg / kg / day as the initial amount and 100 to 1000 μg / kg / day with sustained release for 8 hours. In certain embodiments of the invention, the initial dose of AVP receptor agonist may be about 1-50 μg / kg / day as the initial amount and 20-50 μg / kg / day with 8 hours sustained release. .

Desirably, neither a CRF receptor agonist nor an AVP receptor agonist is administered during the first period associated with each administration of an AVP receptor antagonist. However, in certain embodiments of the invention, the CRF receptor agonist and / or AVP receptor agonist is administered in one or more of the second time periods associated with each administration of the CRF receptor antagonist. Suitable CRF receptor agonists and AVP receptor agonists are undesirable for patients negatively associated with AVP receptors using AVP antagonist administration according to this embodiment of the invention as described earlier herein. Mental, neurological or physiological conditions may be treated. Examples of undesirable mental, neurological or physiological conditions that are negatively associated with the AVP receptor and can be treated using this method include, for example, atypical depression, weight gain and bulimia, Examples include fatigue and fatigue. In desirable embodiments of the invention, upregulation of the AVP system provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions negatively associated with AVP receptors.

In another embodiment of the present invention, the mu and / or delta opiate receptor antagonist is combined with the AVP antagonist in the first period such that the ratio of the administration half-life to the period between administrations is ½ or less. Be administered. Methods of administration of mu and / or delta opiate receptor antagonists and their benefits are as described earlier in this specification.
Immune System Related Conditions The methods of the present invention are useful for treating and / or treating immune related conditions associated with a type of receptor of the neurotransmitter system. In these methods, the immune system is upregulated. Examples of immune-related conditions that can be treated or treated using the methods of the invention include cancer, in particular, autoimmune diseases, innate immune deficiencies, immunodeficiencies due to immunosuppressant therapy, and acquired immune deficiencies. Examples of specific autoimmune diseases include rheumatoid arthritis, multiple sclerosis, generalized lupus erythematosus, Addison disease, ALS (Lau Gehrig's disease), Alzheimer's disease, ankylosing spondylitis, autism spectrum disorder, Autoimmune hemolytic anemia, autoimmune progesterone dermatitis, Behcet's disease, celiac disease, chronic fatigue syndrome, Churg Strauss disease (allergic granulomatous vasculitis), Crest syndrome, Crohn's disease, dermatomyositis, diabetes, qi (COPD), endometriosis, fibromyalgia, Goodpasture's disease, Graves' disease, Hashimoto's thyroiditis, interstitial granulomatous dermatitis, irritable bowel syndrome (IBS), mixed connective tissue disease, self Immune-related connective tissue disease, myasthenia gravis, Parkinson's disease, pemphigoid, pernicious anemia, primary lateral sclerosis (PLS), polychondritis (recurrent) Polymyalgia rheumatica, polymyositis, psoriasis, sarcoidosis, scleroderma, Sjogren's syndrome, transverse myelitis, ulcerative colitis, vasculitis, Wegener's granulomas, and autoimmune diseases following the infection process, Vaccine administration or environmental reactions (for example, reactions to chemicals such as silicone) can be mentioned. According to one embodiment of the invention, the condition to be treated by the method is an infectious microorganism such as a bacterium, fungus, parasite, mycobacteria, yeast, chlamydia, protozoa, helminth, rickettsia, or such as HIV, Infections with viruses such as influenza, hepatitis (types A, B, C), respiratory syncytial virus (RSV), gastrointestinal virus infection, encephalitis, and myocarditis. According to another embodiment of the invention, the immune system-related condition is administration of a vaccine, and upregulation of the immune system increases the production of antibodies against the substances targeted by the vaccine.

  In a particularly desirable embodiment of the invention, the neurotransmitter system is the endogenous endorphin system and the receptor type is a delta opiate receptor that is negatively associated with an immune system-related condition generally undesirable. The ligand is a delta opiate receptor antagonist and counteradaptation causes upregulation of the immune system. Any of the delta opiate receptor antagonists previously described herein can be useful in this embodiment of the invention. In some embodiments of the invention, the delta opiate receptor antagonist is not naltrexone or naloxone. In some desirable embodiments of the invention, the initial dosage of delta opiate receptor antagonist is greater than 10 mg / dose, greater than 10.5 mg / dose, greater than 11 mg / dose, or 15 mg / dose. Exceed. The delta opiate receptor antagonist is desirably a delta receptor selective antagonist, desirably substantially less active against the mu receptor. One example of a suitable delta receptor antagonist is the structure:

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  As described above in relation to mood, immune system function may be reduced during the first period associated with each administration of the ligand. Further, when performed in a manner similar to that described with reference to FIG. 6, immune system function may be reduced during the initial period of continuous administration. Accordingly, it may be desirable to administer one or more additional medicaments during these periods. For example, it may be desirable to administer the immunizing agent in combination with the ligand during the first period and / or during the period of continuous ligand administration. Examples of suitable autoimmune therapies include medications such as corticosteroids, chlorambucil, cyclosporine, cycloformamide, methotrexate, azathioprine, TNFα antagonists, and treatments such as systemic enzyme therapy, gene therapy and radiation therapy. Of course, as will be appreciated by those skilled in the art, other autoimmune drugs, including those developed in the future, can be used in the methods of the present invention. In certain embodiments of the invention, autoimmune therapy is not performed during the second period.

  Similarly, it may be desirable to administer the antiviral agent in combination with the ligand during the first period and / or during the period of continuous ligand administration. Examples of suitable antiviral agents include interferon, ribavirin, protease inhibitors, amantadine, rimantadine, pleconaril, antibodies (monoclonal, anti-VAP, receptor anti-idiotype, foreign receptor, and synthetic receptor mimics), acyclovir , Zidovudine, lamivudine, RNAase H inhibitors, integrase inhibitors, inhibitors of transcription factor adsorption to viral DNA, so-called “antisense” molecules, synthetic ribozymes, zanamivir, and osletamivir. Of course, as will be appreciated by those skilled in the art, other antiviral agents, including those developed in the future, can be used in the methods of the present invention. In certain embodiments of the invention, the antiviral agent is not administered during the second period.

  Similarly, it may be desirable to administer antibacterial, antifungal, and / or anti-neoplastic agents in combination with a ligand during the first period and / or during the period of continuous ligand administration. In certain embodiments of the invention, antibacterial, antifungal, and / or anti-neoplastic agents are not administered during the second period.

  It may be desirable to administer the anti-cancer agent in combination with the ligand during the first period and / or during the period of continuous ligand administration. Suitable anti-cancer agents include, for example, adriamycin, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide, mechloretamine, melphalan, procarbazine, temozolamide, daunorubicin, doxorubicin, idarubicin, bleomycin, mitomycin, mitomycin tacitramine, pricamycin, , Fluorouracil, hydroxyurea, methotrexate, asparaginase, pegase pargase, irinotecan, topotecan, bicalutamide, estramustine, flutamide, leuprolide, megestrol, nilutamide, testosterone, triptorelin, anastrazol, letrozole, aldesleukin, alemtuzumab, Gemtuzumab, toremifene, trastuzumab, Toposide, docetaxel, paclitaxel, vinblastine, vincristine, vinorelbine, altretamine, erlotinib, greebeck, curcumin, tamoxifen, bortezomib, gefitinib, imatinib, 3,4-methylenedioxy-5,4'-dimethoxy-3'-amino-Z -Stilbene derived cancer cell growth inhibitor, hydroxyphenstatin and its sodium diphosphate prodrug, histone deacetylase inhibitor, suberoylanilide hydroxamic acid, trichostatin A, sodium butyrate, metformin, 5-lipoxygenase (5- LO) antagonists, antisense oligonucleotides targeting the RIα regulatory subunit of protein kinase A type I, vitamin E and its analogs, vitamin E succina (VES), as well as gene therapy. Of course, as will be appreciated by those skilled in the art, other antiimmune drugs, including those developed in the future, can be used in the methods of the present invention. In certain embodiments of the invention, the antiviral agent is not administered during the second period.

  Cancer is one undesirable immune-related condition that can be treated and / or treated using the methods described herein. In one desirable embodiment of the invention, the upregulation of the immune system utilizes endogenous administration of endorphins utilizing repeated administration of the delta opiate receptor antagonists described hereinabove to treat or treat cancer. This is achieved by up-regulating the system. Both cancer cells and immune cells (ie killer cells) have opiate receptors. When the immune system is up-regulated, it increases the ability of killer cells to “attack” cancer cells. A further benefit is that up-regulated cancer cells are more susceptible to cell death. Desirably, the method described in the context of FIG. 6 is used, in which case a continuous administration of the ligand is first applied to induce upregulation of the immunization in a relatively rapid manner. The continuous administration time may be in the range of 1 day to several weeks to several months, for example, depending on the severity of the cancer.

  In addition to simply inhibiting the increase in cancer cell proliferation by anticancer agents, there are additional advantages to using opiate antagonists simultaneously with anticancer agents. Since cancer cells proliferate more rapidly when induced, cancer cells are more susceptible to the effects of anticancer agents. That is, the anticancer agent can enhance the toxic effect on the cancer cells during this period in which the cancer cells rapidly proliferate. The anticancer agent induces cancer cell death more efficiently by this method.

  The methods described in the present invention can also be used to treat and / or treat immune diseases and infections. In one desirable embodiment of the invention, the upregulation of the immune system utilizes endogenous administration of endorphins utilizing repeated administration of the delta opiate receptor antagonists described hereinabove to treat or treat cancer. This is achieved by up-regulating the system. In a manner similar to the initiation of cancer treatment, the initiation of treatment with short-term continuous receptor inhibition may be selected as described above with reference to FIG.

  For example, counteradaptive responses to opiate antagonists are upregulation of the immune system. The upregulated immune system enhances the immune response by immune cells such as killer cells, and other immune cells. Such an up-regulated immune system can be used to treat conditions having an abnormal immune system. These immune diseases include, but are not limited to, autoimmune diseases, innate immune deficiencies, immunodeficiencies due to immunosuppressant therapy (ie cancer, for transplantation), and acquired immune deficiencies (ie AIDS). You can choose. An up-regulated immune system may be an additional benefit to enhance the body's ability to fight off infections such as bacterial and viral infections.

  An autoimmune disease is one in which the immune system functions abnormally, producing an immune response against the body's own tissues. Autoimmune diseases are the result of the immune system becoming active against normal cells and cellular components, and as the immune system increases, the activity on the self tissue increases, so such diseases should be exacerbated. It was broken. On the other hand, autoimmune disease has been shown to respond favorably to immune system strengthening.

  One embodiment of the present invention provides a relatively high dose of delta opiate antagonist (ie, naloxone or naltrexone, more than 10 mg, etc., in amounts greater than 10 mg) due to the relatively strong upregulation of the endogenous endorphin system. Used) and thereby up-regulate the immune system relatively strongly.

  For many infections, a second additional benefit is realized if a method similar to that described with reference to FIG. 6 is performed early in continuous receptor inhibition. For example, viral infection during this period of receptor inhibition increases viral particle proliferation due to suppression of the immune system. This benefit can be obtained by administering an agent that kills or inhibits the virus during the period of replication. Viral particles grow more rapidly, making them more sensitive to drugs that inhibit growth and kill it. In this case, if the virus is aggressive, the virus is attacked at the time of replication, so the antiviral agent becomes more powerful. Taking advantage of the period of continuous receptor inhibition, the up-regulated immune system has the added benefit of more powerful destruction of the virus particles in which immune cells remain. Such accompanying antiviral agents include interferon, ribavirin, one of a number of protease inhibitors, amantadine, rimantadine, pleconaril, antibodies (monoclonal anti-VAP, receptor anti-idiotype foreign receptors and synthetic receptor mimetics), Acyclovir, zidovudine (AZT), lamivudine, RNAase H inhibitor, integrase inhibitor, inhibitor of transcription factor adsorption to viral DNA, so-called “antisense” molecules, synthetic ribozymes, zanamivir (Relenza®) )), And Osletamivir (Tamiflu®). As will be appreciated by those skilled in the art, any suitable antiviral agent can be used.

The methods of the invention may be used in a prophylactic manner, i.e. to reduce the likelihood of infection with a potential infectious microorganism or virus. The method of the present invention may be performed, for example, before surgery to reduce the risk of infection during and after surgery. The method of the invention can be used as a prophylactic measure against virtually any infectious substance such as HIV, hepatitis, influenza, RSV, tuberculosis, protozoa, rickettsia, malaria and staphylococci.
Other Conditions In accordance with another aspect of the present invention, cardiovascular or lipid or cholesterol metabolism related conditions such as cardiovascular disorders (eg, cardiovascular, peripheral blood vessels) using the methods described above of the present invention. And / or stroke). The methods of the invention are also useful for treating or treating diabetes (eg, type I and type II).

  Impaired lipid or cholesterol metabolism generally predisposes to CV and diabetes disorders. Lipid or cholesterol metabolism related disorders that can be treated or treated using the methods of the present invention include hypertriglyceridemia, hypercholesterolemia (overall cholesterol and / or low density lipoprotein [LDL] cholesterol elevation, or Unusually low levels of high density lipoprotein [HDL] cholesterol). Lipid metabolism disorders further include lipodystrophy due to HIV (AIDS virus) infection.

  As previously described, the AVP neurotransmitter system is involved in stress, the ACTH / cortisol pathway, and mood disorders such as depression and anxiety. A different and very specific type of stress is called "nutrient stress". Nutritional stress is a stress state caused by fasting, starvation, or insulin hypoglycemia. Nutritional stress results in an increase in glucocorticoid levels (cortisol). However, unlike traditional stress, CRF release does not play an important role in cortisol release in nutritional stress. Instead, AVP is the main regulator of cortisol release in response to nutritional stress.

  Nutritional stress is essential when discussing factors associated with longevity. It was discovered 70 years ago that caloric restriction (which induces nutritional stress) can extend the life of an organism by about 30%. This phenomenon has been demonstrated to occur in many mammals such as rats, mice, dogs and possibly primates. In fact, caloric restriction is the only method that has been shown to extend the life of an organism.

  Caloric restriction is called SIR2 in yeast and appears to act by activating a gene known as SIRT1 in mammals. The SITRT1 gene encodes the enzyme Sirt1, which targets proteins that control critical processes such as apoptosis (cell death), cell defense and metabolism. In other words, Sirt1 appears to be a key regulator of the aging regulatory system that is activated by stress.

  For example, Sirt1 is a central metabolic regulator in liver, muscle and adipocytes. This indicates that Sirt1 is involved in fat accumulation and thus is associated with aging and metabolic diseases such as type 2 diabetes. Another critical process that is modified by Sirt1 is inflammation. Caloric restriction is known to suppress excessive inflammation associated with aging processes such as heart disease and neurodegeneration. Sirt1 further regulates the production of IGF-1 (insulin-like growth factor). IGF-1 is known to affect the life span of various organisms: worms, flies, mice and possibly humans.

  Compounds that modulate the activity of Sir2 and its human congeners are collectively referred to as “sirtuins”. A sirtuin activating compound may be abbreviated as “STAC”. One such STAC is a reservoir troll. Common to red wine and various plants that have been stressed. In fact, some of the health benefits from red wine are likely due to reservoir trolls and / or other STACs. There are many (at least 18) additional compounds produced by plants that modulate sirtuins in response to stress.

  One aspect of the present invention relates to a method that mimics the physiological control mechanism by calorie restriction to activate the Sirt1 pathway. Either method of the present invention applies intermittent stress to the patient, and therefore any method of the present invention activates the Sirt1 pathway, thereby causing adverse conditions associated with the Sirt1 pathway, such as aging, It will be useful to treat or treat conditions related to fat metabolism, inflammation and the IGF-1 system. Such conditions include, for example, cancer, arthritis, asthma, heart disease, and neurodegeneration. The method of the present invention may be used as a means for preventing physiological changes caused by aging. Any of the previously described neurotransmitter systems can be used by one skilled in the art to activate the Sirt1 pathway.

  Caloric restriction is one way of inducing what is called a “holmetic” effect or morphosis. In 1904, Starling created the term “hormone” to refer to substances that are produced in small quantities and transported in the blood to affect other organs. It comes from “Horumo” which means “excited” in Greek. By Southam and Erlich, high concentrations of oak bark extract were found to inhibit fungal growth, but at low doses, stimulated fungal growth (Phytopathology 33: 517, 1943). They improved Stalin's word to “holmosis”, which indicates that low-dose poisons are healthy. Hormesis has been further generalized as a term referring to the long-term benefit of mild repetitive stress or stimulation.

  One feature of hormesis is that it can be activated using specific stimuli. Mild stress, such as increased external temperature, mild radiation exposure or hypergravity, and nutritional stress (ie, calorie restriction [Frame LT, et al., “Calographic Restriction as a Mechanical Resistance to Environmental Dissemination”, “Environmental Disease”). Health Perspect 1998, 106 (Suppl 1): 303-324]) have all been shown to improve a range of parameters related to aging. Since caloric restriction cannot be easily achieved, there has been a trend to develop compounds that mimic the effects of caloric restriction. Such compounds have been referred to as “caloric restriction mimetics” (Weindruch R., et al., “Coloric Restriction Mimetics-Metabolic Interventions”, Journals of Genetics Science and Biosciences A: Biologics Sci. 20-33).

  That is, it is not only caloric restriction that induces physiological parameters that improve age-related conditions. Low levels of intermittent stress can also induce physiological parameters that act as defense mechanisms. In this regard, mild intermittent stress may be beneficial to the organism because it induces physiological parameters to confer improved host defense mechanisms.

  In accordance with one aspect of the present invention, intermittent administration of neurotransmitter receptor ligands is used to induce mild intermittent stress while activating the defense mechanism and causing organisms to undergo multiple stresses. To prevent. A neurotransmitter system that leads to discomfort may be utilized to mimic caloric restriction using the methods described earlier in this specification. For example, all of the nervous systems described earlier in this specification are associated with unpleasant stress conditions. Thus, all of the methods, neurotransmitter systems and ligands described earlier in this specification may be used to induce mild transient stress, thereby inducing a hormetic effect and reducing caloric restriction. You may mimic the effect. In certain embodiments of the invention, these defense mechanisms prevent multiple stresses in the organism to age, fat metabolism, inflammation and the IGF-1 system such as cancer, arthritis, asthma, heart disease and It works to improve neurodegeneration.

  Motor performance is associated with various neurotransmitter systems, such as the endogenous endorphin system. The body produces endorphins in response to exercise. Intensity and level of exercise training are directly related to the endorphin response (Mougin et al, Eur J App Physiol, 1998; Doiron, et al, J Str Cond Res, 1999; Sforzo, Sport Med, 1989; and Golbfarb, et al. , Sport Med, 1997). Because highly trained athletes and high levels of exercise intensity are directly related to endorphin release, it is advantageous to improve athletic performance with an up-regulated endorphin system. Accordingly, one aspect of the present invention relates to improving athletic performance using the methods, neurotransmitter systems and ligands previously described herein. In addition, since continuous receptor inhibition in a short period of time can be advantageous for the previously described cancer treatment, infection treatment and autoimmune therapy, those skilled in the art will be described during exercise training, for example in light of FIG. As has been done, continuous receptor inhibition in a short period of time may be utilized. According to one embodiment of the invention, the neurotransmitter system is the endogenous endorphin system, the ligand is a mu and / or delta opiate receptor antagonist, and the counteradaptation is an upregulation of the endogenous endorphin system.

  Cognition (eg learning and memory) is also directly related to neurotransmitter systems, such as the endogenous endorphin system. (Riley, et al, Neurosci Biobehav Rev, 1980; Getsova, et al, Neurosci Behave Physiol, Biomed & Life Sci & Russian Library 6). Acute administration of a delta opiate receptor antagonist (eg, naltrexone) inhibits learning and memory (Chaves, et al., Neuropsychology, 1988). The fact that circulating glucocorticoid levels are associated with cognitive function and persistently high levels of cortisol are associated with memory impairment further indicated an association between neurotransmitter system and cognition (Li, et al., Neurobio Aging, 2005). On the other hand, temporary rises in glucocorticoids improve learning and memory tasks (Patel, et al., Neurol Aging, 2002). Accordingly, one aspect of the present invention relates to improving cognition using the methods, neurotransmitter systems and ligands described hereinabove. For example, these methods may be used to cause only a temporary rise in glucocorticoid. Any of the methods, neurotransmitter systems and ligands described earlier in this specification are used to cause mild intermittent stress while also causing a transient increase in glucocorticoids. Cognition can be improved using any of the methods, neurotransmitter systems and ligands previously described herein. In another example, to improve cognition, one of skill in the art performs up-regulation of the endogenous system using the mu and / or delta opiate receptor antagonists described hereinabove. Can do. In addition, short-term continuous receptor inhibition can be advantageous for the previously described cancer treatments, infection treatments and autoimmune therapies, so to improve cognitive function more rapidly, one skilled in the art, for example Short-term continuous receptor inhibition may be utilized as described with reference to FIG.

  Those skilled in the art will recognize that various modifications and changes may be made to the present invention without departing from the spirit and scope of the invention. In other words, the present invention is intended to cover improvements and modifications of the present invention provided that they fall within the scope of the appended claims and their equivalents. All references cited herein are hereby incorporated by reference in their entirety.

FIG. 3 is a graph of ligand concentration (part a) and mood versus time (part b) in vivo according to one embodiment of the invention. FIG. 4 is a graph of mood versus time for several doses of a ligand according to another embodiment of the invention. Graph of in vivo ligand concentration versus time for a single dose administration of a ligand with a relatively long compound half-life. Graph of in vivo ligand concentration versus time for administration with a time-release transdermal patch of a ligand having a relatively short compound half-life. Graph of ligand concentration versus time in vivo when the patch is removed during administration in administration with a timed release transdermal patch of a ligand having a relatively short compound half-life. FIG. 6 is a graph of ligand concentration (part a) and mood versus time (part b) in vivo according to another embodiment of the invention.

Claims (374)

A method of modulating a neurotransmitter system containing a type of receptor by inducing counter-adaptation in a patient comprising:
Repeatedly administering a ligand for said one type of receptor to a patient, each dose having a half-life of administration, said ligand being bound to that type of receptor in a first period associated with each administration; To induce, maintain or improve counter adaptation by
The counteradaptation causes the regulation of the neurotransmitter system;
The ratio of the half-life of administration to the period between administrations is ½ or less.   2. The counter-adaptation is induced by administering to the patient a ligand for the one type of receptor prior to repeated administration of the ligand to the patient, and the counter-adaptation is maintained or improved by repeated administration of the ligand. Method.   3. A method according to claim 1 or 2, wherein modulation of the neurotransmitter system has a therapeutic effect with respect to undesirable mental, neurological or physiological conditions associated with the one type of receptor.   The method according to any one of claims 1 to 3, wherein the ligand is an agonist for a receptor of the receptor type, and the modulation is down-regulation of the neurotransmitter system.   5. The method of claim 4, wherein an undesirable mental condition, neurological condition or physiological condition is positively associated with said type of receptor. The counter adaptation is
Reduced biosynthesis or release of neurotransmitters that bind to receptors of said receptor type,
Increased reuptake of neurotransmitters that bind to receptors of said receptor type,
A reduction in the number of said one type of receptor and / or the number of binding sites on said type of receptor; and
6. The method according to any one of claims 4-5, wherein the method is at least one of a decrease in the sensitivity of the receptor type to binding by a natural neurotransmitter and / or receptor agonist. .   7. The method of any one of claims 4-6, wherein an antagonist to the receptor type of receptor is not administered during a first period associated with each administration.   Each administration has a second period associated with the administration, the second period follows the first period associated with the administration, and the antagonist for the receptor type of receptor is one of those second periods. 8. A method according to any one of claims 4 to 7, wherein the method is administered in one or more.   4. The method according to any one of claims 1 to 3, wherein the ligand is an antagonist to a receptor of the receptor type and the modulation is an upregulation of the neurotransmitter system.   10. The method of claim 9, wherein an undesirable mental state, neurological state or physiological state is negatively associated with said type of receptor. The counter adaptation is
Increased biosynthesis or release of neurotransmitters that bind to receptors of said receptor type,
Reduced reuptake of neurotransmitters that bind to receptors of said receptor type,
An increase in the number of said one type of receptor and / or the number of binding sites on said type of receptor, and
11. The method according to claim 9 or 10, wherein the method is at least one of increased sensitivity of the receptor to binding by at least one of a ligand and a receptor agonist.   12. A method according to any one of claims 9 to 11, wherein an agonist for the receptor type of receptor is not administered during a first period associated with each administration.   Each administration has a second period associated with the administration, the second period follows the first period associated with the administration, and the agonist for the receptor type of receptor is a member of the second period. 13. A method according to any one of claims 9 to 12, wherein the method is administered in one or more.   14. A method according to any one of claims 1 to 13, wherein a substantial number of receptors of the receptor type are bound by the ligand in each first period.   15. The method of claim 14, wherein at least about 30% of the receptor is bound by the ligand in each first period.   15. The method of claim 14, wherein at least about 50% of the receptor is bound by the ligand in each first period.   15. The method of claim 14, wherein at least about 75% of the receptor is bound by the ligand in each first period.   15. The method of claim 14, wherein at least about 90% of the receptor is bound by the ligand in each first period.   19. A method according to any one of the preceding claims, wherein the duration of each first period is at least about 5 minutes.   19. A method according to any one of the preceding claims, wherein the duration of each first period is at least about 30 minutes.   19. A method according to any one of the preceding claims, wherein the duration of each first period is at least about 1 hour.   19. A method according to any one of the preceding claims, wherein the duration of each first period is at least about 2 hours.   19. A method according to any one of the preceding claims, wherein the duration of each first period is at least about 4 hours.   24. The method of any one of claims 1 to 23, wherein the duration of each first period is less than about 24 hours.   24. The method of any one of claims 1 to 23, wherein the duration of each first period is less than about 16 hours.   24. The method of any one of claims 1 to 23, wherein the duration of each first period is less than about 12 hours.   24. The method of any one of claims 1 to 23, wherein the duration of each first period is less than about 8 hours.   24. The method of any one of claims 1 to 23, wherein the duration of each first period is less than about 6 hours.   Each administration has a second period associated with the administration, the second period follows the first period associated with the administration, and in each second period a substantial number of the receptors remain unbound by the ligand. The method according to any one of claims 1 to 28.   30. The method of claim 29, wherein about 50% or less of the receptor is bound by a ligand in each second period.   30. The method of claim 29, wherein about 25% or less of the receptor is bound by a ligand in each second period.   30. The method of claim 29, wherein no more than about 10% of the receptor is bound by a ligand in each second period.   33. The method of any one of claims 13-18 or 29-32, wherein the duration of each second period is at least about 2 hours.   33. The method of any one of claims 13-18 or 29-32, wherein the duration of each second period is at least about 10 hours.   33. The method of any one of claims 13-18 or 29-32, wherein the duration of each second period is at least about 15 hours.   33. The method of any one of claims 13-18 or 29-32, wherein the duration of each second period is about 20 hours or less.   33. A method according to any one of claims 13-18 or 29-32, wherein the duration of each second period is about 30 hours or less.   33. The method of any one of claims 13-18 or 29-32, wherein the duration of each second period is about 50 hours or less.   40. The method according to any one of claims 1 to 39, wherein the ratio of the half-life of administration to the period between doses is 1/3 or less.   40. The method according to any one of claims 1 to 39, wherein the ratio of the half-life of administration to the period between administrations is 1/5 or less.   40. The method according to any one of claims 1 to 39, wherein the ratio of the half-life of administration to the period between administrations is 1/8 or less.   40. The method according to any one of claims 1 to 39, wherein the ratio of the half-life of administration to the period between administrations is 1/12 or less.   43. The method according to any one of claims 1-42, wherein the ratio of the half-life of administration to the period between doses is greater than 1/24.   43. The method of any one of claims 1-42, wherein the ratio of the half-life of administration to the period between doses is greater than 1/12.   43. The method according to any one of claims 1-42, wherein the ratio of the half-life of administration to the period between doses is greater than 1/8.   43. The method of any one of claims 1-42, wherein the ratio of the half-life of administration to the period between doses is greater than 1/5.   43. The method of any one of claims 1-42, wherein the ratio of the half-life of administration to the period between doses is greater than 1/4.   43. The method of any one of claims 1-42, wherein the ratio of the half-life for administration to the period between doses is greater than 1/3.   49. The method of any one of claims 1-48, wherein the dosage of ligand at each administration increases with time.   50. The method according to any one of claims 1 to 49, wherein the dose of ligand at each administration increases intermittently with time.   51. The method of claim 50, wherein the dosage is increased with a period of one week or more between increases.   51. The method of claim 50, wherein the dosage is increased with a period of 2 weeks or more between increases.   51. The method of claim 50, wherein the dosage is increased with a period of 3 weeks or more between increases.   51. The method of claim 50, wherein the dosage is increased with a period of one month or more between increases.   51. The method of claim 50, wherein the dosage is increased with a period of two months or more between increases.   51. The method of claim 50, wherein the dosage is increased with a period of 3 months or more between increases.   51. The method of claim 50, wherein the dosage is increased with a period of 6 months or more between increases.   51. The method of claim 50, wherein the dosage is increased with a period of one year or more between increases.   59. The method of any one of claims 50-58, wherein at each increase in dosage, the dosage is increased by at least 5% of the initial dosage.   59. A method according to any one of claims 50 to 58, wherein at each increase in dosage, the dosage is increased by at least 10% of the initial dosage.   59. The method of any one of claims 50-58, wherein at each increase in dosage, the dosage is increased by at least 25% of the initial dosage.   59. A method according to any one of claims 50 to 58, wherein at each increase in dosage, the dosage is increased by at least 50% of the initial dosage.   59. A method according to any one of claims 50 to 58, wherein at each increase in dosage, the dosage is increased by at least 100% of the initial dosage.   64. The method of any one of claims 50 to 63, wherein the maximum dose is within 300 times the initial dose.   64. The method of any one of claims 50 to 63, wherein the maximum dose is within 100 times the initial dose.   64. The method according to any one of claims 50 to 63, wherein the maximum dose is within 50 times the initial dose.   64. The method according to any one of claims 50 to 63, wherein the maximum dose is within 20 times the initial dose.   68. The method of any one of claims 1 to 67, wherein administration of the ligand is performed daily.   69. The method according to any one of claims 1 to 68, wherein the period between administrations is 2 days or more.   69. The method according to any one of claims 1 to 68, wherein the period between administrations is 3 days or more.   69. The method according to any one of claims 1 to 68, wherein the period between administrations is 5 days or more.   69. The method of any one of claims 1 to 68, wherein the period between administrations is 1 week or longer.   69. The method according to any one of claims 1 to 68, wherein the period between administrations is 2 weeks or more.   69. The method according to any one of claims 1 to 68, wherein the period between administrations is 1 month or longer.   75. The method of any one of claims 1 to 74, wherein the half-life for administration is less than about 16 hours.   75. The method of any one of claims 1 to 74, wherein the half-life for administration is less than about 12 hours.   75. The method of any one of claims 1 to 74, wherein the half-life for administration is less than about 8 hours.   75. The method of any one of claims 1 to 74, wherein the half-life for administration is less than about 4 hours.   79. The method of any one of claims 1 to 78, wherein the dosing half-life is greater than about 4 hours.   79. The method of any one of claims 1 to 78, wherein the dosing half-life is greater than about 12 hours.   79. The method of any one of claims 1 to 78, wherein the dosing half-life is greater than about 16 hours.   79. The method of any one of claims 1 to 78, wherein the half-life of administration is longer than about 30 hours.   83. The method of any one of claims 1 to 82, wherein the ligand has a compound half-life of less than about 16 hours.   83. The method of any one of claims 1 to 82, wherein the ligand has a compound half-life of less than about 12 hours.   83. The method of any one of claims 1 to 82, wherein the ligand has a compound half-life of less than about 8 hours.   83. The method of any one of claims 1 to 82, wherein the ligand has a compound half-life of less than about 4 hours.   90. The method of any one of claims 1 to 86, wherein the ligand has a compound half-life of greater than about 4 hours.   87. The method of any one of claims 1 to 86, wherein the ligand has a compound half-life of greater than about 16 hours.   87. The method of any one of claims 1 to 86, wherein the compound has a compound half-life greater than about 30 hours.   87. The method of any one of claims 1 to 86, wherein the compound half-life of the ligand is greater than about 12 hours. The compound has a compound half-life greater than about 12 hours, the method comprising:
93. The method of claim 90, further comprising the step of repeatedly administering a second ligand for the one type of receptor with a cycle shorter than every 2 days, wherein each administration of the second ligand has a dose half-life of less than about 8 hours. The method described.   92. The method of claim 91, wherein the ligand having a compound half-life of greater than about 12 hours is an agonist and the second ligand is an agonist.   92. The method of claim 91, wherein the ligand having a compound half-life of greater than about 12 hours is an antagonist and the second ligand is an antagonist.   94. The method of any one of claims 1 to 93, wherein the administration is repeated at least 5 times.   94. The method of any one of claims 1 to 93, wherein the administration is repeated at least 10 times.   94. The method of any one of claims 1 to 93, wherein the administration is repeated at least 25 times.   94. The method of any one of claims 1 to 93, wherein the administration is repeated at least 50 times.   98. The dose of the ligand is sufficient to cause a counteradaptive response, but low enough so that the direct effect of ligand-receptor binding is low and acceptable to the patient. 2. The method according to item 1.   99. The method of any one of claims 1 to 98, wherein a substantial portion of the first period occurs during patient sleep.   100. The method of any one of claims 1 to 99, wherein at least 40% of the first period occurs during patient sleep.   100. The method of any one of claims 1 to 99, wherein at least 60% of the first period occurs during patient sleep.   100. The method of any one of claims 1 to 99, wherein at least 85% of the first period occurs during patient sleep.   103. The method of any one of claims 1-102, wherein each administration of the ligand is performed within a certain time before the patient goes to bed.   103. The method of any one of claims 1-102, wherein each administration of the ligand is performed prior to 1 hour before the patient goes to bed.   Each administration of the ligand is performed by oral administration, transdermal administration, inhalation administration, subcutaneous administration, intravenous administration, intramuscular administration, intravertebral administration, intrathecal administration, transmucosal administration, or The method according to any one of claims 1 to 104, which is performed using any one of an osmotic pump, a microcapsule, an implant, and a suspension.   106. The method according to any one of claims 1 to 105, further comprising administering an anxiolytic in combination with the ligand.   107. The method of claim 106, wherein the anxiolytic agent affects the GABA pathway.   107. The method of claim 106, wherein the anxiolytic agent is benzodiazepine.   109. The method of claim 108, wherein the benzodiazepine is selected from the group consisting of diazepam, lorazepam, alprazolam, temazepam, flurazepam, and chlordiazepoxide.   110. The method of any one of claims 1-109, further comprising administering a sleeping pill in combination with the ligand. In combination with the ligand, TCA, MAOI, SSRI, NRI, SNRI, CRF modulator, serotonin presynaptic autoreceptor antagonist, 5HT ₁ agonist, dynorphin antagonist, GABA-A modifier, serotonin 5H _2C and 5H _2B modifier 111. The method of any one of claims 1-110, further comprising administering a compound selected from the group consisting of at least one of: a beta-3 adrenergic receptor agonist, an NMDA antagonist, a V1B antagonist, a GPCR modifying agent, and a substance P antagonist. 2. The method according to item 1.   111. The method of claim 111, wherein the compound is selected from the group consisting of fluoxetine, paroxetine, sertraline, fluvoxamine, citalopram, escitalopram, venlafaxine, and reboxetine.   113. The method of any one of claims 1-112, further comprising performing autoimmune therapy in a first period in combination with the ligand.   114. The autoimmune therapy is selected from the group consisting of corticosteroids, chlorambucil, cyclosporine, cyclophosphamide, methotrexatate, azathioprine, TNFα antagonists, systemic enzyme therapy, gene therapy, and radiation therapy. The method described.   114. The method of claim 113, wherein autoimmune dosing is not performed during the second period.   113. The method of any one of claims 1-112, further comprising administering an antiviral agent in a first period in combination with the ligand.   The antiviral agent is interferon, ribavirin, protease inhibitor, amantadine, rimantadine, pleconaril, antibody (monoclonal, anti-VAP, receptor anti-idiotype, foreign receptor, and synthetic receptor mimic), acyclovir, zidovudine (AZT) ), Lamivudine, RNAase H inhibitor, integrase inhibitor, inhibitor of transcription factor adsorption to viral DNA, antisense molecule, synthetic ribozyme, zanamivir, and osletamivir. Method.   117. The method of claim 116, wherein autoimmune dosing is not performed during the second period.   113. The method of any one of claims 1-112, further comprising administering an antimicrobial agent in a first period in combination with the ligand.   120. The method of claim 119, wherein the antimicrobial agent is not administered during the second period.   113. The method of any one of claims 1-112, further comprising administering an antifungal agent in a first period in combination with the ligand.   122. The method of claim 121, wherein the antimicrobial agent is not administered during the second period.   113. The method of any one of claims 1-112, further comprising administering an antitumor agent in combination with the ligand in a first period.   124. The method of claim 123, wherein the anti-tumor agent is not administered during the second period.   113. The method of any one of claims 1-112, further comprising administering an anticancer agent in a first period in combination with the ligand.   126. The method of claim 125, wherein the anticancer agent is not administered during the second period.   The anticancer agent is adriamycin, busulfan, carboplatin, chlorambucil, cisplatin, cyclophosphamide, ifosfamide, mechlorethamine, melphalan, procarbazine, temozolamide, daunorubicin, doxorubicin, idarubicin, bleomycin, mitomycin, mitoxatron, pricamycin, cytaracylfluoro, Urea, methotrexate, asparaginase, pegaspargase, irinotecan, topotecan, bicalutamide, estramustine, flutamide, leuprolide, megestrol, nilutamide, testosterone, triptorelin, anastrazole, letrozole, aldesleukin, alemtuzumab, toremifumab, toremifumab Trastuzumab, etoposide, doce Xel, paclitaxel, vinblastine, vincristine, vinorelbine, altretamine, erlotinib, grebec, curcumin, tamoxifen, bortezomib, gefitinib, imatinib, 3,4-methylenedioxy-5,4'-dimethoxy-3'-amino-Z-stilbene Cancer cell growth inhibitor derived from, hydroxyphenstatin and its sodium diphosphate prodrug, histone deacetylase inhibitor, suberoylanilide hydroxamic acid, trichostatin A, sodium butyrate, metformin, 5-lipoxygenase (5-LO) Antagonists, antisense oligonucleotides targeting the RIα regulatory subunit of protein kinase A type I, vitamin E and its analogs, vitamin E succinate (VES), 127. The method of claim 126, wherein the method is selected from the group consisting of: gene therapy. The neurotransmitter system is the SP system;
The kind of receptor is an SP receptor;
The ligand is an SP receptor agonist;
128. The method according to any one of claims 1 to 127, wherein the counter adaptation causes down-regulation of the SP system. The counter adaptation is
Decreased biosynthesis or release of SP, NKA, and / or NKB, either at the end of the receptor or by the pituitary gland.
A reduction in the number of receptors and / or the number of binding sites on the receptors; and
129. The method of claim 128, wherein the method is at least one of reduced sensitivity of the receptor to binding by an SP receptor agonist, at least one of SP, NKA, and NKB.   129. The method of any one of claims 128 to 129, wherein the SP receptor agonist is a peptide system.   129. The method according to any one of claims 128 to 129, wherein the SP receptor agonist is an analog of at least one of SP, NKA, and NKB, or a pharmaceutically acceptable salt or derivative thereof. The SP receptor agonist is substance P; substance P, free acid; biotin-substance P; [Cys _3,6 , Tyr ₈ , Pro ₉ ] -substance P; (disulfide bridge: 3-6), [Cys _{3, 6} , Tyr ₈ , Pro ₁₀ ] -Substance P; (Disulfide Bridge: 3-6), [4-Chloro-Phe _7,8 ] -Substance P; [4-Benzoyl-Phe ₈ ] -Substance P; [Succinyl- 129. Asp ₆ , N-Me-Phe ₈ ] -Substance P (6-11) (Senstide); [Tyr ₈ ] -Substance P; [Tyr ₉ ] -Substance P; or Shark Substance P peptide. 129. The method of any one of -129.   The SP receptor agonist is an NKA analog or NKB analog having a C-terminal heptapeptide similar to either NKA (4-10) and NKB (4-10), or a pharmaceutically acceptable salt thereof, or 129. The method according to any one of claims 128 to 129, which is a carrier. The SP receptor agonist is [Gln ⁴ ] -NKA, [Gln ⁴ ] -NKA (4-10), [Phe ⁷ ] -NKA, [Phe ⁷ ] -NKA (4-10), [Ile ⁷ ]- ^{NKA, [Ile7] -NKA (4-10} ), [Lys 5, MeLeu 9, Nle 10] -NKA (4-10), [Nle 10] -NKA (4-10), β-Ala8] -NKA ( 4-10), [Ala ⁵ ] -NKA (4-10), [Gln ⁴ ] -NKB, [Gln ⁴ ] -NKB (4-10), [Phe ⁷ ] -NKB, [Phe ⁷ ] -NKB ( 4-10), [Ile ⁷ ] -NKB, [Ile ⁷ ] -NKB (4-10), [Lys ⁵ , MeLeu ⁹ , Nle ¹⁰ ] -NKB (4-10), [Nle ¹⁰ ] -NKB (4 -10), β-Ala8] ^{NKB (4-10), [Ala 5} ] -NKB (4-10), GR73,632 [ delta - Aminobareriru [Pro9, N-Me-Leu10 ] - substance P (7-11)], [Glu (OBzl) 11] The method according to any one of claims 128 to 129, which is substance P and hemokinin 1 (HK-1) (substance P homolog), or a pharmaceutically acceptable salt or carrier thereof.   129. The method of any one of claims 128-129, wherein the SP receptor agonist is [Arg] -NKB, or a pharmaceutically acceptable salt or carrier thereof. 129. The method of any one of claims 128-129, wherein the SP receptor agonist is an NKA analog or NKB analog having Val ⁷ substituted with MePhe, or a pharmaceutically acceptable salt or carrier thereof. .   The initial dose of the SP receptor agonist is about 0.1 to 100 µg / kg / day as an initial amount, and 100 to 1000 µg / kg / day by sustained release for 8 hours. The method according to item.   The initial dose of the SP receptor agonist is about 1 to 50 µg / kg / day as an initial amount, and 20 to 50 µg / kg / day by sustained release for 8 hours. The method described.   138. The method of any one of claims 128-136, wherein the method is used to treat an undesired mental, neurological or physiological condition in a patient.   Said undesired mental, neurological or physiological condition may be chronic pain, mood disorders, eating disorders, anxiety disorders, desire disorders, drug abuse disorders, inflammatory conditions, nausea or vomiting, urinary incontinence, rash, 140. The method of claim 139, wherein the method is erythema or rash.   Said undesirable mental, neurological or physiological condition is fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, chronic cancer pain, shingles, reflex sympathetic dystrophy, neuropathy 140. The method of claim 139, wherein the method is inflammatory pain.   140. The method of claim 139, wherein the undesirable mental, neurological, or physiological condition is pain that is expected to occur in the future.   142. The method of claim 141, wherein the pain expected to occur in the future is pain from a medical procedure or pain from physical movement.   The undesirable mental state, neurological state or physiological state is major depression, post-traumatic depression, transient depressed mood, manic depression, mood modulation disorder, generalized mood disorder, unpleasant feeling 140. The method of claim 139, wherein the disease is non-organismal dysfunction.   140. The method of claim 139, wherein the undesirable mental, neurological or physiological condition is binge eating, obesity, anorexia nervosa or bulimia.   The undesired mental, neurological or physiological condition may be generalized anxiety, panic disorder, phobia, obsessive compulsive disorder, attention deficit hyperactivity disorder, Tourette syndrome, hysteria sleep disorder, or respiratory related 140. The method of claim 139, wherein the method is a sleep disorder.   140. The method of claim 139, wherein the undesirable mental, neurological or physiological condition is a lack of motivation due to learning or memory problems.   Said undesirable mental, neurological or physiological condition is an abuse of a drug selected from the group consisting of hypnotics, alcohol, nicotine, stimulants, anxiolytics, central nervous depressants, hallucinogens and marijuana 140. The method of claim 139.   140. The method of claim 139, wherein the undesirable mental, neurological or physiological condition is asthma, arthritis, rhinitis, colitis, inflammatory bowel disease, skin or mucosal inflammation, or acute pancreatitis.   140. The method of claim 139, wherein the undesirable mental condition, neurological condition or physiological condition is nausea or vomiting caused by chemotherapy.   The method according to any one of claims 128 to 150, wherein the method is used as an auxiliary treatment for cancer.   154. The method of any one of claims 128-151, wherein the SP receptor antagonist is not administered during the first period associated with each administration.   153. The method of any one of claims 128-152, wherein the SP receptor antagonist is administered in one or more of the second time periods.   The SP receptor antagonists are SR48968, L-760735, CP-96,345, NKP608, L-AT, MK-869, L-742,694, L-733060, CP-99,994, P-122,721 155, CP122,171, GSK597599, GSK679769, GSK823296, Saleduant, Talnetant, Osanethant, and pharmaceutically acceptable salts, analogs and derivatives thereof.   The initial dose of the SP receptor antagonist is 12 mg / kg / hour for 8 hours for L-760735, about 30 μg / kg / hour for CP-96,345, 0.1-10 mg / kg / dose for SSR240600, NKP608, 0.01-0.1 mg / kg / dose, L-AT, 1-10 mg / kg / dose, MK-869, 0.01-3 mg / kg / dose, L-742,694, 1-30 mg / kg / dose 154 which corresponds to 1 kg / dose, 1-10 mg / kg / dose for L-733,060, 3-30 mg / kg / d for CP-99,994 or CP-122,721, and about 100 mg / dose for saledantant The method described in 1.   156. The method of any one of claims 128-155, wherein the down-regulation of the SP system provides a therapeutic effect with respect to an undesirable mental, neurological or physiological condition. The neurotransmitter system is the endogenous endorphin system;
The kind of receptor is at least one of a mu opiate receptor and a delta opiate receptor,
The ligand is at least one of a mu opiate receptor antagonist and a delta opiate receptor antagonist;
128. A method according to any one of claims 1 to 127, wherein the counter-adaptation causes an upregulation of the endogenous endorphin system. The counter adaptation is
Increased biosynthesis or release of endorphins, either at the end of the receptor or by the pituitary gland,
Of increasing the number of the receptors and / or the number of endorphin binding sites on the receptor, and increasing the sensitivity of the receptors to binding by at least one of a mu opiate agonist, a delta opiate agonist and an endorphin. 158. The method of claim 157, wherein there is at least one. The counter adaptation is
Increase in biosynthesis or release of endorphins at the end of the receptor and increase in biosynthesis or release of endorphins by the pituitary gland, and increase in the number of receptors and / or the number of endorphin binding sites on the receptors 159. The method according to any one of claims 157 to 158, which is at least one of them.   160. The method of any one of claims 157 to 159, wherein at least one of the mu opiate receptor antagonist and the delta opiate receptor antagonist is a specific mu receptor antagonist or a specific delta receptor antagonist.   At least one of the mu opiate receptor antagonist and delta opiate receptor antagonist is crocinnamox mesylate, CTAP, CTOP, etonizenenyl isothiocyanate, β-funaltrexamine hydrochloride, naloxonazine dihydrochloride, cyprodim, and 160. The method of any one of claims 157 to 159, which is a specific mu opiate receptor antagonist selected from the group consisting of pharmaceutically acceptable salts, analogs and derivatives thereof.   At least one of the mu opiate receptor antagonist and the delta opiate receptor antagonist is naltrindole, N-benzylnaltrindole HCl, BNTX maleate, ICI-154,129, ICI-174,864, naltriben mesylate, SDM25N 160. A specific delta opiate receptor antagonist selected from the group consisting of HCl, 7-benzylidenenaltrexone, and pharmaceutically acceptable salts, analogs and derivatives thereof, according to any one of claims 157 to 159. the method of.   The method according to any one of claims 157 to 159, wherein at least one of the mu opiate receptor antagonist and the delta opiate receptor antagonist is a non-specific opiate antagonist.   160. The mu opiate receptor antagonist and / or delta opiate receptor antagonist is naloxone, naltrexone, nalmefene or nalbuphine, or a pharmaceutically acceptable salt or derivative thereof, according to any one of claims 157 to 159. The method described. The delta opiate receptor antagonist is a compound having the following structure:

Wherein R is allyl, methylallyl, cyclopropylmethyl, dimethylallyl, tetrahydrofurfuryl, or cyclobutylmethyl;
R ¹ is H, (C ₁ -C ₁₈ hydrocarbyl)-, (C ₁ -C ₁₈ hydrocarbyl) -CO-, (C ₁ -C ₁₈ hydrocarbyl) ₂ N-CO-, (C ₁ -C ₁₈ hydrocarbyl) _{-SO 2 -, (C 1 ~C} 18 _{hydrocarbyl) -O-CO-, Ph-CO-} , Ph-SO 2 -, a Ph-NH-CO, the Ph _{is, (C} 1 _{~C 12} hydrocarbyl) One or more substituents independently selected from the group consisting of: (C ₁ -C ₁₂ hydrocarbyl) -O—, Cl, F, Br, I, CF ₃ , R ⁴ O—, and R ⁴ ₂ N— Each R ⁴ is independently selected from the group consisting of H, (C ₁ -C ₄ alkyl), H—CO—, and (C ₁ -C ₄ alkyl) —CO—. ,
Each R ^2a and R ^2b is H, (C ₁ -C ₆ alkyl), (C ₁ -C ₆ alkyl) -O—, (C ₁ -C ₆ alkyl) —CO—O—, R ⁵ —O—. Independently selected from the group consisting of R ⁵ ₂ N—, R ⁵ —CO—NH—, R ⁵ —S—, and NO ₂ , each R ⁵ is H, (C ₁ -C ₆ alkyl), _(C 3 _{-C 10 cycloalkyl), (C} 6 ~C _{10 aryl) (C} 1 _{~C 6 alkyl) -CO -, (C 3 ~C} 10 _{cycloalkyl) -CO -, (C 6 ~C} 10 aryl ) —CO— independently selected from the group consisting of —CO—, and R ⁵ is (C ₁ -C ₁₂ hydrocarbyl), (C ₁ -C ₁₂ hydrocarbyl) -O—, Cl, F, Br, I, CF _{3, respectively.} 1 to 3 substituents selected from the group consisting of R ⁴ O—, and R ⁴ ₂ N— Are optionally substituted, or R ^2a and R ^2b together form O═ or CH ₂ ═,
R ³ is H, OH, CH ₃ , or OCH ₃ ),
160. The method according to any one of claims 157 to 159, wherein the N-oxide or a pharmaceutically acceptable salt thereof.   166. The method of claim 165, wherein R is allyl. R ¹ is The method of claim 165 or 166 is not a H. The method of claim 165 or 166 R ¹ is o- aminobenzoyl or o- (acetyloxy) benzoyl. R ¹ is _(C 1 _{-C 18} alkyl) or _(C 1 _{-C 18} alkyl) CO- The method according to claim 165 or 166. The method of claim 165 or 166 R ¹ is CO- _(C 1 ~C ₆ alkyl). R ^2a and ^{R 2a} method according to any one of claims 165-170 which do not form a O = together. R ^2a and ^{R 2a} method according to any one of claims 165-170 that form a CH ₂ = or is H, or together. R ³ is The method according to any one of claims 165 to 172 are not OH.   178. The initial dose of at least one of the mu opiate receptor antagonist and / or delta opiate receptor antagonist corresponds to between about 2 mg / dose and about 200 mg / dose for naloxone, according to any one of claims 161-173. the method of.   178. The initial dose of at least one of the mu opiate receptor antagonist and delta opiate receptor antagonist corresponds to between about 10 mg / dose and about 100 mg / dose for naloxone according to any one of claims 161-173. The method described.   159. The method of any one of claims 157 to 158, wherein at least one of the mu opiate receptor antagonist and delta opiate receptor antagonist is naloxone, or a pharmaceutically acceptable salt or prodrug thereof.   177. The method of claim 176, wherein each dose of naloxone is greater than 10 mg / dose, greater than 10.5 mg / dose, greater than 11 mg / dose, or greater than 15 mg / dose.   178. The method of claims 176-177, wherein the initial dose of naloxone is 10-50 mg / dose.   178. The method of claims 176-177, wherein the initial dose of naloxone is 5-500 mg / dose.   179. The method of claims 176-179, wherein the maximum dose of naloxone is 3000 mg / dose or less.   181. The method of any one of claims 157 to 180, wherein the mu opiate receptor antagonist and / or delta opiate receptor antagonist is administered using a timed release formulation or a sustained release formulation.   At least one of the mu opiate receptor antagonist and the delta opiate receptor antagonist is oral administration, transdermal administration, intrathecal administration, intrathecal administration, inhalation administration, subcutaneous administration, intravenous administration, intramuscular administration, transmucosal 181. The method according to any one of claims 157 to 180, wherein the method is administered by any of the pharmacological administrations, or via any of osmotic pumps, microcapsules, implants, suspensions.   181. The method according to any one of claims 157 to 180, wherein at least one of the mu opiate receptor antagonist and the delta opiate receptor antagonist is administered transdermally.   186. Any one of claims 181-183, wherein the mu opiate receptor antagonist and / or delta opiate receptor antagonist is released over a duration of 2-12 hours, 2-6 hours, or 6-12 hours. The method described in 1.   181. The method of any one of claims 157 to 180, wherein the mu opiate receptor antagonist and / or delta opiate receptor antagonist is administered as a rapidly absorbed loading dose.   The mu opiate receptor antagonist and / or the delta opiate receptor antagonist is administered using both rapidly absorbed loading and transdermal, timed release, or sustained release dosage forms. The method according to any one of Items 157 to 180.   187. The specific mu receptor antagonist and / or delta receptor antagonist and the non-specific mu receptor antagonist and / or delta receptor antagonist are administered at about the same time. 2. The method according to item 1.   187. The specific mu receptor antagonist and / or delta receptor antagonist, and the non-specific mu receptor antagonist and / or delta receptor antagonist are administered sequentially, any of claims 157-186. The method according to claim 1.   Said undesired mental, neurological or physiological condition is pain, mood disorders, eating disorders, anxiety disorders, dysphoria, drug abuse disorders, lack of motivation or ability, immune system related conditions, and treatment 188. The method according to any one of claims 157 to 188, wherein the wound is a necessary wound.   188. The method according to any one of claims 157 to 189, wherein the method is used to treat an undesired mental, neurological or physiological condition in a patient.   191. The method of claim 190, wherein the undesirable mental condition, neurological condition, or physiological condition is expected to occur in the future, chronic pain syndrome, or acute pain.   The undesired mental, neurological or physiological condition may be pain expected to occur in future surgery, pain expected to occur in future physical exercise, fibromyalgia, chronic fatigue syndrome 191. The method of claim 190, wherein the disease is chronic back pain, chronic headache, shingles, reflex sympathetic dystrophy, neuropathy, inflammatory pain, or chronic cancer pain.   The undesirable mental state, neurological state or physiological state is major depression, post-traumatic depression, transient depressed mood, manic depression, mood modulation disorder, generalized mood disorder, unpleasant feeling 191. The method of claim 190, wherein the disease is non-organ sexual dysfunction.   191. The method of claim 190, wherein the undesirable mental, neurological or physiological condition is binge eating, obesity, anorexia nervosa or bulimia.   191. The method of claim 190, wherein the undesirable mental, neurological or physiological condition is generalized anxiety, panic disorder, Tourette syndrome, hysterical sleep disorder, or respiratory related sleep disorder.   191. The method of claim 190, wherein the undesirable mental, neurological or physiological condition is a lack of motivation due to learning or memory problems.   Said undesirable mental, neurological or physiological condition is an abuse of a drug selected from the group consisting of hypnotics, alcohol, nicotine, stimulants, anxiolytics, central nervous depressants, hallucinogens and marijuana 191. The method of claim 190.   191. The method of claim 190, wherein the undesirable mental state, neurological state, or physiological state is a drive or lack of preparation for an intended mental or physical activity.   199. The method of claim 198, wherein the intended activity is physical education, athletics, learning, or testing.   199. The method according to any one of claims 157 to 199, wherein the method is used as an adjunct treatment for cancer, infection, AIDS, or wound.   212. The method of any one of claims 157 to 200, wherein at least one of the mu opiate receptor agonist and the delta opiate receptor agonist is not administered during a first period associated with each administration.   202. The method of any one of claims 157 to 201, wherein at least one of a mu opiate receptor agonist and a delta opiate receptor agonist is administered in one or more of the second time periods.   202. The method of any one of claims 157-201, wherein the CRF receptor antagonist is administered in one or more of the second time periods.   The CRF receptor antagonists include R121919, DMP696, antalalmine, CP-154,526, SSR125543A, 2-arylamino-4-trifluoromethylaminomethylthiazole antagonists, astresin, alpha-helical CRF compounds, and their pharmaceutically acceptable 204. The method of claim 203, selected from the group consisting of salts, analogs, and derivatives that can be made.   The CRF receptor agonist is repeatedly administered in combination with at least one of the mu opiate receptor antagonist and / or the delta opiate receptor antagonist, each administration of the CRF receptor agonist has a dosing half-life, and 205. The method according to any one of claims 157 to 204, wherein the ratio of dosing half-life is ½ or less.   205. The method of any one of claims 157 to 204, wherein the CRF receptor agonist is administered in one or more of the second time periods.   205. Upregulation of the endogenous endorphin system results in a therapeutic effect with respect to undesirable mental, neurological or physiological conditions associated with at least one of mu opiate receptors and delta opiate receptors. The method of any one of these. The neurotransmitter system is a dynorphin system,
The kind of receptor is a kappa receptor;
The ligand is a kappa receptor agonist;
128. The method according to any one of claims 1 to 127, wherein the counter adaptation causes down regulation of the dynorphin system. The counter adaptation is
Reduced dynorphin biosynthesis or release, either at the end of the receptor or by the pituitary gland
A reduction in the number of kappa receptors and / or the number of binding sites on the kappa receptors; and
209. The method of claim 208, wherein the method is at least one of reduced sensitivity of the kappa receptor to binding by at least one of a kappa receptor agonist and dynorphin.   The method according to any one of claims 208 to 209, wherein the kappa receptor agonist is a peptide system.   209. The method of any one of claims 208 to 209, wherein the kappa receptor agonist is dynorphin, or a pharmaceutically acceptable salt, carrier, or analog thereof.   The kappa receptor agonists are non-benzomorphan; enadrine; PD117302; CAM569; PD123497; GR89,696; U69,593; TRK-820; trans-3,4-dichloro-N-methyl-N- [1- ( 1-pyrrolidinyl) cyclohexyl] benzene-acetamide; asimadoline (EMD-61753); benzeneacetamide; thiomorpholine; piperidine; benzo [b] thiophene-4-acetamide; trans-(+/-)-(PD-117302); -Benzofuranacetamide (PD-129190); 2,6-methano-3-benzazocin-8-ol (MR-1268); morphinan-3-ol (KT-90); GR-45809; 1-piperazinecarboxylic acid (GR) -89696 GR-94845; piperzaine; GR-94839; xorphanl; benzeneacetamide (RU-49679); fedotodine; benzeneacetamide (DuP-747); HN-11608; apadrin (RP-60180); Spiradoline mesylate; benzeneacetamide trans-U-50488 methane sulfate; 3FLB; FE200655; FE200663; analogs of either MPCB-GRRI and MPCB-RRI, similar to the C-terminal fragment of dynorphin A (1-8) 209. The method of any one of claims 208 to 209, wherein the body is a body, or a pharmaceutically acceptable salt or carrier thereof.   The initial dose of the kappa receptor agonist is 0.0005 to 0.05 mg / kg / dose for dynorphin, 5 to 700 mg / dose for enadrine, 1 to 500 μg / dose for FE20665, 0.5 to 100 μg / dose; 0.01 to 1 mg / kg / dose for U69,593, 0.05 to 5 mg / kg / dose for TRK-820, 0.01 to 1 mg / kg / dose for U50,488, 0.01 to 1 mg / kg for PD117302 213. A method according to any one of claims 208 to 212 corresponding to kg / dose.   The initial dose of the kappa receptor agonist is 0.005-0.02 mg / kg / dose for dynorphin, 100-500 mg / dose for enadrine, 3-100 μg / dose for FE20665, 1-80 μg / dose for FE20666, 0.1 to 0.7 mg / kg / dose for U69,593, 0.5 to 3 mg / kg / dose for TRK-820, 0.5 to 7 mg / kg / dose for U50 and 488, 0.1 to 0.1 for PD117302 The method according to any one of claims 208 to 212, which corresponds to 0.7 mg / kg / dose.   223. The method of any one of claims 208 to 212, wherein the kappa receptor agonist is salvinorin A or an analog or prodrug thereof.   227. The method of claim 215, wherein the initial dose of salvinorin A is 5 to 200 [mu] g / dose.   227. The method according to any one of claims 215 to 216, wherein the maximum dose of salvinorin A is at least 5000 [mu] g / dose.   227. The method of any one of claims 215 to 217, wherein salvinorin A is administered transmucosally.   219. The method according to any one of claims 215 to 218, wherein salvinorin A is administered as a sustained release formulation.   220. The method of claim 219, wherein salvinorin A is administered over a duration of 2-6 hours.   223. The method of any one of claims 208-220, wherein the peptide-based kappa receptor agonist and the non-peptide-based kappa receptor agonist are administered substantially simultaneously.   The method according to any one of claims 208 to 220, wherein the peptide-based kappa receptor agonist and the non-peptide-based kappa receptor agonist are administered sequentially.   223. The method according to any one of claims 208 to 222, wherein the method is used to treat an undesired mental, neurological or physiological condition of a patient.   224. The method of claim 223, wherein the condition is any of pain, mood disorders, eating disorders, anxiety disorders, craving abnormalities, drug abuse disorders, and lack of motivation or ability.   224. The method of claim 223, wherein the condition is expected to occur in the future, chronic pain syndrome, or acute pain.   The condition may be pain expected to occur in future surgery, pain expected to occur in future physical exercise, fibromyalgia, chronic fatigue syndrome, chronic back pain, chronic headache, shingles, reflex complications 224. The method of claim 223, wherein the method is sensory dystrophy, neuropathy, inflammatory pain, or chronic cancer pain.   The condition is major depression, post-traumatic depression, transient depressed mood, manic depression, dysthymic disorder, generalized mood disorder, anxiety, or non-organism dysfunction. 223. The method according to 223.   224. The method of claim 223, wherein the condition is overeating, obesity, anorexia nervosa or bulimia.   224. The method of claim 223, wherein the condition is generalized anxiety, panic disorder, Tourette syndrome, hysteria sleep disorder, or respiratory related sleep disorder.   224. The method of claim 223, wherein the condition is a lack of motivation due to learning or memory problems.   224. The method of claim 223, wherein the condition is an abuse of a drug selected from the group consisting of sleeping pills, alcohol, nicotine, stimulants, anxiolytics, central nervous depressants, hallucinogens and marijuana.   224. The method of claim 223, wherein the condition is a willingness or lack of preparation for an intended mental or physical activity.   233. The method of claim 232, wherein the intended activity is physical education, athletics, learning, or testing.   234. The method according to any one of claims 208 to 233, wherein the method is used as an adjunct therapy for cancer.   235. The method of any one of claims 208-234, wherein the kappa receptor antagonist is not administered during a first period associated with each administration.   235. The method of any one of claims 208 to 234, wherein the kappa receptor antagonist is administered in one or more of the second time periods.   237. The method of any one of claims 208 to 236, wherein the down-regulation of the dynorphin system provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions associated with kappa receptors. The neurotransmitter system is a serotonin system,
128. The method of any one of claims 1 to 127, wherein the counter adaptation causes a serotonin system up-regulation. The kind of receptor is a serotonin presynaptic autoreceptor,
238. The method of claim 238, wherein the ligand is a serotonin presynaptic autoreceptor agonist. The counter adaptation is
An increase in the biosynthesis and release of serotonin in the synaptic cleft,
Reduced serotonin reuptake,
A decrease in the number of serotonin presynaptic autoreceptors,
Reduced sensitivity of the serotonin presynaptic autoreceptor to at least one of serotonin and a serotonin presynaptic autoreceptor agonist;
An increase in the number of serotonin post-synaptic receptors, and
240. The method of claim 239, wherein the method is at least one of increased sensitivity of a serotonin post-synaptic receptor to either serotonin and a serotonin post-synaptic receptor agonist. The method according to any one of claims 239 to 240, wherein the serotonin presynaptic autoreceptor is at least one of 5HT _1A autoreceptor and 5HT _1B autoreceptor.   247. The serotonin presynaptic autoreceptor agonist is any of EMD-68843, basspirone, gepirone, ipsapirone, tandospirone, resopitron, zarospirone, MDL-73005EF, and BP-554. The method described.   The initial dose of the serotonin presynaptic autoreceptor agonist is 1 to 400 mg / dose for EMD-68843, 1 to 500 mg / dose for buspirone, 1 to 500 mg / dose for resepitron, 1 to 500 mg / dose for gepirone, and 1 to 500 mg / dose for tandospirone. The method according to any one of claims 239 to 242, which corresponds to 5 to 500 mg and 1 to 200 mg for zalospirone.   The initial dose of the serotonin presynaptic autoreceptor is 10-100 mg / dose for EMD-68843, 10-100 mg / dose for buspirone, 10-200 mg / dose for resepitron, 10-100 mg / dose for gepirone, 20 for tandospirone. 245. The method according to any one of claims 239 to 242 which corresponds to ~ 200mg and 10 ~ 100mg for Zalospirone.   245. The method of any one of claims 239-244, wherein the serotonin presynaptic autoreceptor antagonist is not administered during the first period associated with each administration.   245. The method of any one of claims 239-244, wherein the serotonin presynaptic autoreceptor antagonist is administered in one or more of the second time periods. The kind of receptor is a serotonin post-synaptic receptor,
238. The method of claim 238, wherein the ligand is a serotonin post-synaptic receptor antagonist. The counter adaptation is
An increase in the biosynthesis and release of serotonin in the synaptic cleft,
Reduced serotonin reuptake,
An increase in the number of serotonin post-synaptic receptors,
Increased sensitivity of serotonin and post-synaptic receptor agonists to serotonin and / or serotonin post-synaptic receptor agonists;
A decrease in the number of serotonin presynaptic autoreceptors, and
247. The method of claim 247, wherein the method is at least one of reduced sensitivity of a serotonin presynaptic autoreceptor to at least one of serotonin and a serotonin presynaptic autoreceptor agonist. The serotonin post-synaptic receptors are 5HT ₁ receptor, 5HT ₂ receptor, 5HT ₃ receptor, 5HT ₄ receptor, 5HT ₅ receptor, 5HT ₆ receptor, 5HT ₇ receptor, and their subtype receptors. 249. A method according to any one of claims 247 to 248, wherein the method is any of the bodies.   The serotonin post-synaptic receptor antagonist is any of (S) -WAY-100135, WAY-100635, basspirone, gepirone, ipsapirone, tandospirone, resopitron, zarospirone, MDL-73005EF, and BP-554. 249. The method according to any one of 249.   251. The method of any one of claims 247-250, wherein the initial dose of the serotonin post-synaptic receptor antagonist corresponds to about 0.01-5 mg / kg / dose for WAY-100635.   251. The method of any one of claims 247-250, wherein the initial dose of the serotonin post-synaptic receptor antagonist corresponds to about 0.025-1 mg / kg / dose for WAY-100635.   254. The method of any one of claims 247-252, further comprising administering a serotonin presynaptic autoreceptor agonist in combination with the serotonin post-synaptic receptor antagonist.   253. The method of any one of claims 247-252, wherein the serotonin post-synaptic receptor antagonist is also a serotonin pre-synaptic receptor agonist.   254. The method of any one of claims 247-254, wherein the serotonin post-synaptic receptor agonist is not administered during a first period associated with each administration.   259. The method of any one of claims 247-255, wherein the serotonin post-synaptic receptor agonist is administered in one or more of the second time periods.   256. The method of any one of claims 238-256, further comprising administering at least one of a norepinephrine presynaptic alpha-2 adrenergic receptor agonist and a norepinephrine post-synaptic adrenergic receptor agonist in combination with the ligand. The method described.   258. The method of any one of claims 238-257, wherein the upregulation of the serotonin system provides a therapeutic effect with respect to an undesirable mental, neurological or physiological condition associated with the receptor. The neurotransmitter system is a norepinephrine system;
128. The method of any one of claims 1 to 127, wherein the counter adaptation causes norepinephrine system up-regulation. Said type of receptor is a norepinephrine presynaptic alpha-2 adrenergic receptor;
259. The method of claim 259, wherein the ligand is a norepinephrine presynaptic alpha-2 adrenergic receptor agonist. The counter adaptation is
An increase in the biosynthesis and release of norepinephrine in the synaptic cleft,
Reduced reuptake of norepinephrine,
A decrease in the number of norepinephrine presynaptic alpha-2 adrenergic receptors,
Reduced sensitivity of norepinephrine presynaptic alpha-2 adrenergic receptors to at least one of norepinephrine and norepinephrine presynaptic alpha-2 adrenergic receptor agonists;
An increase in the number of norepinephrine post-synaptic adrenergic receptors, and
262. The method of claim 260, wherein the method is at least one of increased sensitivity of a norepinephrine post-synaptic adrenergic receptor to at least one of norepinephrine and a norepinephrine post-synaptic adrenergic receptor agonist.   261. The norepinephrine presynaptic alpha-2 adrenergic receptor agonist is any one of clonidine, guanfacine, lofexidine, detomidine, dexmedetomidine, mibazelol, and alpha-methylnoradrelin. The method described in 1.   The initial dose of the norepinephrine presynaptic alpha-2 adrenergic receptor agonist is 0.1-10 μg / kg / dose for clonidine, 0.01-10 mg / dose for guanfacine, 0.01-1 mg / d for lofexidine. Equivalent to 1 to 100 μg / dose for detomidine, 0.05 to 5 μg / dose for dexmedetomidine, 0.05 to 10 μg / kg / dose for mibazelol, 5 to 500 ng / kg / dose for alpha-methyl noradrenylline 263. A method according to any one of claims 260 to 262.   The initial dose of the norepinephrine presynaptic alpha-2 adrenergic receptor agonist is 0.1-0.5 mg / dose for clonidine, 0.1-5 mg / dose for guanfacine, 0.05-0.5 mg for lofexidine. / Dose, 10-80 μg / kg / dose for detomidine, 0.1-3 μg / kg / dose for dexmedetomidine, 0.5-5 μg / kg / dose for mibazelol, 10-100 ng / kg for alpha-methyl noradrenine 263. A method according to any one of claims 260 to 262, corresponding to administration.   263. The method of any one of claims 260-262, wherein the norepinephrine presynaptic alpha-2 adrenergic receptor antagonist is not administered in the first phase associated with each administration.   268. The method of any one of claims 260-263, wherein the norepinephrine presynaptic alpha-2 adrenergic receptor antagonist is administered in one or more of the second time periods. Said kind of receptor is a norepinephrine post-synaptic adrenergic receptor,
The ligand is a norepinephrine post-synaptic adrenergic receptor antagonist;
259. The method of claim 259, wherein the undesirable mental state, neurological state or physiological state is negatively associated with a norepinephrine post-synaptic adrenergic receptor. The counter adaptation is
Any increase in biosynthesis and release of norepinephrine in the synaptic cleft,
Reduced norepinephrine reuptake;
Increased number of norepinephrine post-synaptic adrenergic receptors,
Increased sensitivity of norepinephrine post-synaptic adrenergic receptors to at least one of norepinephrine and norepinephrine post-synaptic adrenergic receptor agonists;
A decrease in the number of norepinephrine presynaptic alpha-2 adrenergic receptors, and
268. The method of claim 267, wherein the method is at least one of reduced sensitivity of a norepinephrine presynaptic alpha-2 adrenergic receptor to at least one of norepinephrine and a norepinephrine presynaptic alpha-2 adrenergic receptor agonist.   273. The method of any one of claims 267-268, wherein the norepinephrine post-synaptic adrenergic receptor is any of alpha receptors, beta receptors, and subtypes thereof.   269. The method of any one of claims 267 to 269, wherein the norepinephrine post-synaptic adrenergic receptor antagonist is any of idazoxan, SKF104078, and SKF104856.   270. The method of any one of claims 267-270, wherein the initial dose of the norepinephrine post-synaptic adrenergic receptor antagonist corresponds to 0.5-100 mg / dose for idazoxan.   275. The method of any one of claims 267-270, wherein the initial dose of the norepinephrine post-synaptic adrenergic receptor antagonist corresponds to 5-50 mg / dose for idazoxan.   273. The method of any one of claims 267-272, further comprising administering a norepinephrine presynaptic alpha-2 adrenergic receptor agonist in combination with the norepinephrine post-synaptic adrenergic receptor antagonist.   273. The method of any one of claims 267-272, wherein the norepinephrine post-synaptic adrenergic receptor antagonist is also a norepinephrine pre-synaptic alpha-2 adrenergic receptor agonist.   275. The method of any one of claims 267-274, wherein norepinephrine post-synaptic adrenergic receptor agonist is not administered during the first period associated with each administration.   276. The method of any one of claims 267-275, wherein the norepinephrine post-synaptic adrenergic receptor agonist is administered in one or more of the second time periods.   276. The method of any one of claims 267-276, further comprising administering any of a serotonin pre-synaptic autoreceptor agonist and a serotonin post-synaptic receptor antagonist in combination with the ligand.   281. The method of any one of claims 259-277, wherein the method is used to treat an undesired mental, neurological or physiological condition associated with a serotonin receptor.   295. The method of claim 278, wherein the condition is any of mood disorder, eating disorder, pain disorder, drug abuse disorder, anxiety disorder, and obsessive compulsive disorder.   294. The method according to any one of claims 259 to 278, wherein the method is used as an adjunct therapy for cancer.   294. The method of any one of claims 259-279, wherein the upregulation of the norepinephrine system provides a therapeutic effect with respect to an undesirable mental, neurological or physiological condition associated with the receptor. The neurotransmitter system is a CRF system;
Said kind of receptor is a CRF receptor;
The ligand is a CRF receptor agonist;
128. The method according to any one of claims 1 to 127, wherein the counter adaptation causes a down-regulation of the CRF system. The counter adaptation is
Decreased biosynthesis and release of corticotropin releasing factor by the hypothalamus;
A reduction in the number of CRF receptors and / or the number of binding sites on the CRF receptors, and
283. The method of claim 282, wherein the method is at least one of a decrease in sensitivity of the receptor to binding by a CRF receptor agonist and / or corticotropin releasing factor.   284. The method of any one of claims 282 to 283, wherein the CRF receptor agonist is a peptide system.   289. The method of any one of claims 282 to 283, wherein the CRF receptor agonist is an analog of a corticotropin releasing factor, or a pharmaceutically acceptable salt or derivative thereof.   289. The method of any one of claims 282 to 283, wherein the CRF receptor agonist is cortagine.   The initial dose of the CRF receptor agonist is about 0.1 to 100 µg / kg / day as an initial amount, and 100 to 1000 µg / kg / day by sustained release for 8 hours. The method according to item.   290. The initial dose of the CRF receptor agonist is about 1-50 μg / kg / day as an initial amount, and 20-50 μg / kg / day by sustained release for 8 hours. The method described.   290. The method of any one of claims 282 to 288, wherein the method is used to treat an undesired mental, neurological or physiological condition of a patient positively associated with a CRF receptor.   290. The method of claim 289, wherein the undesirable mental, neurological or physiological condition is melancholic depression.   290. The method of claim 289, wherein the undesirable mental state, neurological state, or physiological state is a lack of memory.   290. The method of claim 289, wherein the undesirable mental state, neurological state, or physiological state is anxiety or an anxiety related disorder.   290. The method of claim 289, wherein the undesirable mental, neurological or physiological condition is bulimia.   290. The method of claim 289, wherein the undesirable mental state, neurological state, or physiological state is a need for memory enhancement that is expected to occur in the future.   290. The method of claim 289, wherein the undesirable mental state, neurological state, or physiological state is a stress that is expected to occur in the future.   290. The method of claim 289, wherein the undesirable mental, neurological or physiological condition is post-traumatic stress disorder.   290. The method of claim 289, wherein the undesirable mental, neurological or physiological condition is anorexia.   290. The method of claim 289, wherein the undesirable mental, neurological or physiological condition is a lack of motivation due to learning or memory problems.   In the method, the ratio of the half-life to the period between doses is ½ or less, and at least one of a mu opiate receptor antagonist and a delta opiate receptor antagonist is combined with the CRF agonist in the first 294. The method of any one of claims 282 to 298, further comprising administering for a period of time.   299. The method of any one of claims 282 to 299, wherein neither a CRF receptor antagonist nor an AVP receptor antagonist is administered during the first period associated with each administration.   321. The method of any one of claims 282 to 300, wherein at least one of a CRF receptor antagonist and an AVP receptor antagonist is administered in one or more of the second time periods associated with each administration.   The CRF receptor antagonists include R121919, DMP696, antalalmine, CP-154,526, SSR125543A, 2-arylamino-4-trifluoromethylaminomethyltriazole antagonists, astresin, alpha-helical CRF compounds, and their pharmaceutically acceptable 320. The method of claim 301, selected from the group consisting of salts, analogs and derivatives that can be made.   331. The method of any one of claims 282 to 302, wherein the down-regulation of the CRF system provides a therapeutic effect with respect to undesirable mental, neurological or physiological conditions positively associated with CRF receptors. The neurotransmitter system is a CRF system;
Said kind of receptor is a CRF receptor;
The ligand is a CRF receptor antagonist;
128. A method according to any one of claims 1 to 127, wherein the counter-adaptation causes an up-regulation of the CRF system. The counter adaptation is
Either increased biosynthesis and release of corticotropin-releasing factor by the hypothalamus,
An increase in the number of CRF receptors and / or the number of binding sites on the CRF receptors, and
305. The method of claim 304, wherein the method is at least one of increased sensitivity of the receptor to binding by a CRF receptor agonist and / or corticotropin releasing factor.   The CRF receptor antagonists include R121919, DMP696, antalalmine, CP-154,526, SSR125543A, 2-arylamino-4-trifluoromethylaminomethyltriazole antagonists, astresin, alpha-helical CRF compounds, and their pharmaceutically acceptable 306. The method according to any one of claims 304 to 305, selected from the group consisting of salts, analogs and derivatives that can be made.   307. The initial dose of the CRF receptor antagonist is about 0.1 to 100 μg / kg / day as an initial amount, and 100 to 1000 μg / kg / day by sustained release for 8 hours. The method according to item.   307. The initial dose of the CRF receptor antagonist is about 1 to 50 μg / kg / day as an initial amount, and 20 to 50 μg / kg / day by sustained release for 8 hours. The method described.   309. The method of any one of claims 304-308, wherein the method is used to treat an undesired mental, neurological or physiological condition in a patient that is negatively associated with a CRF receptor.   309. The method of claim 309, wherein the undesirable mental condition, neurological condition or physiological condition is atypical depression.   309. The method of claim 309, wherein the undesirable mental, neurological or physiological condition is weight gain or bulimia.   309. The method of claim 309, wherein the undesirable mental state, neurological state, or physiological state is fatigue or fatigue.   In the method, the ratio of the half-life to the period between doses is ½ or less, and at least one of a mu opiate receptor antagonist and a delta opiate receptor antagonist is combined with the CRF agonist in the first The method of any one of claims 304-312, further comprising administering for a period of time.   314. The method of any one of claims 304-313, wherein neither a CRF receptor agonist nor an AVP receptor agonist is administered during the first period associated with each administration.   315. The method of any one of claims 304-314, wherein at least one of a CRF receptor agonist and an AVP receptor agonist is administered in one or more of the second time periods associated with each administration.   315. The method of claim 315, wherein the CRF receptor agonist is an analog of corticotropin releasing factor, cortagine, or a pharmaceutically acceptable salt or derivative thereof.   316. The method of any one of claims 304-316, wherein down-regulation of the CRF system provides a therapeutic effect with respect to an undesirable mental, neurological or physiological condition negatively associated with the CRF receptor. The neurotransmitter system is the AVP system;
The kind of receptor is an AVP receptor;
The ligand is an AVP receptor agonist;
128. A method according to any one of claims 1 to 127, wherein the counter-adaptation causes an AVP system down-regulation. The counter adaptation is
Reduction of either arginine vasopressin biosynthesis and release by the hypothalamus,
A reduction in the number of the AVP receptors and / or the number of binding sites on the AVP receptors, and
319. The method of claim 318, wherein the method is at least one of a decrease in the sensitivity of the receptor to binding by an AVP receptor agonist and / or arginine vasopressin.   321. The method of any one of claims 318 to 319, wherein the AVP receptor agonist is a peptide system.   321. The method of any one of claims 318-319, wherein the AVP receptor agonist is selected from the group consisting of ferripressin, desmopressin, and pharmaceutically acceptable salts, analogs, and derivatives thereof.   The initial dose of the AVP receptor agonist is about 0.1 to 100 µg / kg / day as an initial amount, and 100 to 1000 µg / kg / day by sustained release for 8 hours, any one of claims 318 to 321. The method according to item.   321. The initial dose of the AVP receptor agonist is about 1-50 μg / kg / day as an initial amount, and 20-50 μg / kg / day by sustained release for 8 hours, according to any one of claims 318-321. The method described.   324. The method of any one of claims 318-323, wherein the method is used to treat an undesired mental, neurological or physiological condition in a patient positively associated with an AVP receptor.   324. The method of claim 324, wherein the undesirable mental state, neurological state or physiological state is melancholic depression.   324. The method of claim 324, wherein the undesirable mental state, neurological state, or physiological state is a lack of memory.   324. The method of claim 324, wherein the undesirable mental condition, neurological condition, or physiological condition is anxiety or an anxiety related disorder.   325. The method of claim 324, wherein the undesirable mental, neurological or physiological condition is bulimia.   325. The method of claim 324, wherein the undesirable mental state, neurological state or physiological state is a memory enhancement need that is expected to occur in the future.   325. The method of claim 324, wherein the undesirable mental, neurological or physiological condition is a stress that is expected to occur in the future.   329. The method of claim 324, wherein the undesirable mental state, neurological state or physiological state is post-traumatic stress disorder.   325. The method of claim 324, wherein the undesirable mental state, neurological state, or physiological state is anorexia.   325. The method of claim 324, wherein the undesirable mental state, neurological state or physiological state is a lack of motivation due to learning or memory problems.   The method includes combining a mu opiate receptor antagonist and / or a delta opiate receptor antagonist with the AVP receptor agonist such that the ratio of dosing half-life to inter-dosing period is ½ or less. 340. The method of any one of claims 318-333, further comprising administering.   335. The method of claims 318-334, wherein the method further comprises administering a CRF receptor agonist in combination with the AVP receptor agonist such that the ratio of dosing half-life to period between doses is ½ or less. The method according to any one of the above.   325. The method of any one of claims 318-325, wherein neither a CRF receptor antagonist nor an AVP receptor antagonist is administered during the first period associated with each administration.   340. The method of any one of claims 318-336, wherein at least one of a CRF receptor antagonist and an AVP receptor antagonist is administered in one or more of the second time periods associated with each administration. The AVP receptor antagonists, d (CH2) 5Tyr (Me ) AVP, Phaa-d-Tyr (Me) -Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH 2, [Lys (3N 3, Phpa ⁸ ] HO-LVA, [d (CH2) 5, D-Ile2, Ile4] -AVP, [125I] -d (CH2) 5 [D-Tyr (Et) 2, Val4, Tyr-NH29] AVP, OPC -21268 (1- (1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidyl) -3,4-dihydro-2 (1H) -quinolinone), R49059, OPC-31260 (5-dimethylamino -1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine), Koniba Tan, VPA985, and YM471 [(Z) -4 ′-[4,4-difluoro-5- [2- (4-dimethylaminopiperidino] -2-oxoethylidene] -2,3,4,5- 337. selected from the group consisting of tetrahydro-1H-1-benzazepine-1-carbonyl] -2-phenylbenzanilide monohydrochloride), and pharmaceutically acceptable salts, analogs and derivatives thereof. the method of.   340. The method of any one of claims 318-338, wherein the downregulation of the AVP system results in a therapeutic effect with respect to undesirable mental, neurological or physiological conditions associated with AVP receptors. The neurotransmitter system is the AVP system;
The kind of receptor is an AVP receptor;
The ligand is an AVP receptor antagonist;
128. The method of any one of claims 1 to 127, wherein the counter adaptation causes an upregulation of the AVP system. The counter adaptation is
Any increase in biosynthesis and release of arginine vasopressin by the hypothalamus,
An increase in the number of the AVP receptors and / or the number of binding sites on the AVP receptors, and
340. The method of claim 340, wherein the method is at least one of increased sensitivity of the receptor to binding by an AVP receptor agonist and / or arginine vasopressin. The AVP receptor antagonists, d (CH2) 5Tyr (Me ) AVP, Phaa-d-Tyr (Me) -Phe-Gln-Asn-Arg-Pro-Arg-Tyr-NH 2, [Lys (3N 3, Phpa ⁸ ] HO-LVA, [d (CH2) 5, D-Ile2, Ile4] -AVP, [125I] -d (CH2) 5 [D-Tyr (Et) 2, Val4, Tyr-NH29] AVP, OPC -21268 (1- (1- [4- (3-acetylaminopropoxy) benzoyl] -4-piperidyl) -3,4-dihydro-2 (1H) -quinolinone), R49059, OPC-31260 (5-dimethylamino -1- [4- (2-methylbenzoylamino) benzoyl] -2,3,4,5-tetrahydro-1H-benzazepine), Koniba Tan, VPA985, and YM471 [(Z) -4 ′-[4,4-difluoro-5- [2- (4-dimethylaminopiperidino] -2-oxoethylidene] -2,3,4,5- 340-341 selected from the group consisting of tetrahydro-1H-1-benzazepine-1-carbonyl] -2-phenylbenzanilide monohydrochloride), and pharmaceutically acceptable salts, analogs and derivatives thereof. The method of any one of these.   345. The initial dose of the AVP receptor antagonist is about 0.1 to 100 μg / kg / day as an initial amount, and 100 to 1000 μg / kg / day by sustained release for 8 hours. The method according to item.   345. The initial dose of the AVP receptor antagonist is about 1-50 μg / kg / day as an initial amount, and 20-50 μg / kg / day by sustained release for 8 hours. The method described.   345. The method of any one of claims 340-344, wherein the method is used to treat an undesired mental, neurological or physiological condition in a patient that is negatively associated with an AVP receptor.   345. The method of claim 345, wherein the undesirable mental condition, neurological condition, or physiological condition is atypical depression.   345. The method of claim 345, wherein the undesirable mental condition, neurological condition, or physiological condition is weight gain or bulimia.   345. The method of claim 345, wherein the undesirable mental state, neurological state, or physiological state is fatigue or fatigue.   In the method, the ratio of the half-life to the period between doses is ½ or less, and at least one of a mu opiate receptor antagonist and a delta opiate receptor antagonist is combined with the AVP agonist in the first 347. The method of any one of claims 340 to 348, further comprising administering for a period of time.   356. The method of any one of claims 340-350, wherein neither an AVP receptor agonist nor an AVP receptor agonist is administered during the first period associated with each administration.   356. The method of any one of claims 340-350, wherein at least one of the AVP receptor agonist and / or the AVP receptor agonist is administered in one or more of the second time periods associated with each administration.   356. The method of claim 351, wherein the AVP receptor agonist is selected from the group consisting of ferripressin, desmopressin, and pharmaceutically acceptable salts, analogs, and derivatives thereof.   356. The method of any one of claims 340 to 352, wherein downregulation of the AVP system results in a therapeutic effect with respect to undesirable mental, neurological or physiological conditions negatively associated with AVP receptors.   128. The method of any one of claims 1 to 127, wherein the method is used to treat an undesired mental, neurological or physiological condition associated with a receptor of the receptor type. the method of.   356. The method of claim 354, wherein the condition is any of mood disorder, eating disorder, pain disorder, drug abuse disorder, anxiety disorder, and obsessive compulsive disorder.   The method is used to treat or treat a condition associated with an undesirable immune system of a patient in need thereof, the condition associated with the immune system being associated with a receptor of the receptor type, 354. The method of any one of claims 1-353, wherein the method causes upregulation of the immune system.   356. The method of claim 356, wherein the neurotransmitter system is an endogenous endorphin system, the type of receptor is a delta opiate receptor, and the ligand is a delta opiate receptor antagonist.   356. The method of any one of claims 356 to 357, wherein the condition associated with the undesirable immune system is cancer.   356. The method of any one of claims 356 to 357, wherein the condition involving the undesirable immune system is a cancer comprising cancer cells that are substantially free of zeta receptors.   356. The condition according to any one of claims 356 to 357, wherein the condition associated with the undesirable immune system is any of autoimmune disease, innate immune deficiency, immunodeficiency due to immunosuppressant therapy, and acquired immune deficiency. the method of.   The autoimmune diseases are rheumatoid arthritis, multiple sclerosis, generalized lupus erythematosus, Addison's disease, ALS (Lau Gehrig's disease), Alzheimer's disease, ankylosing spondylitis, autism spectrum disorder, autoimmune hemolysis Anemia, autoimmune progesterone dermatitis, Behcet's disease, celiac disease, chronic fatigue syndrome, Churg-Strauss disease (allergic granulomatous vasculitis), Crest syndrome, Crohn's disease, dermatomyositis, diabetes, emphysema (COPD) Endometriosis, fibromyalgia, Goodpascher's disease, Graves' disease, Hashimoto's thyroiditis, interstitial granulomatous dermatitis, irritable bowel syndrome (IBS), mixed connective tissue disease, autoimmune related binding Tissue disease, gravity myasthenia, Parkinson's disease, pemphigoid, pernicious anemia, primary lateral sclerosis (PLS), polychondritis (recurrent), rheumatic Myosodynia, polymyositis, psoriasis, sarcoidosis, scleroderma, Sjogren's syndrome, transverse myelitis, ulcerative colitis, vasculitis, Wegener's granulomas, and infection process, vaccination, or environmental response 356. The method of any one of claims 356 to 357, selected from the group consisting of subsequent autoimmune diseases.   356. The method of any one of claims 356 to 357, wherein the condition associated with the undesirable immune system is an infection.   356. The method of any one of claims 356 to 357, wherein the method is used to reduce the likelihood of infection by an infectious microorganism or virus.   363. The method of claim 363, wherein the method is used to reduce the likelihood of infection by any of bacteria, viruses, fungi, parasites, mycobacteria, yeast, chlamydia, protozoa, helminths, and rickettsia.   356. The method of any one of claims 356 to 357, wherein the immune system-related condition is administration of a vaccine, and wherein the upregulation of the immune system causes an increase in the production of antibodies to a substance targeted by the vaccine. .   The method is used to treat or treat a condition associated with cardiovascular or lipid or cholesterol metabolism in a patient in need thereof, wherein the condition associated with cardiovascular or lipid or cholesterol metabolism is the type of receptor 354. A method according to any one of claims 1 to 353 relating to the receptor.   367. The method of claim 366, wherein the condition associated with cardiovascular or lipid or cholesterol metabolism is a cardiovascular disorder.   The method of claim 366, wherein the condition associated with cardiovascular or lipid or cholesterol metabolism is any of hypertriglyceridemia, hypercholesterolemia, and lipodystrophy due to HIV infection.   128. A method according to any one of claims 1 to 127, wherein the method is used to treat or treat a lack of preparation for future athletic activities.   128. The method of any one of claims 1 to 127, wherein the method is used to treat an undesired mental, neurological or physiological condition associated with a receptor of the receptor type. the method of.   354. The method of any one of claims 1-353, wherein the method is used to treat or treat an undesirable condition associated with the Sirt1 pathway.   371. The method of claim 371, wherein the method is used to treat a condition associated with patient aging.   371. The method of claim 371, wherein the method is selected from the group consisting of fat metabolism, inflammation, cancer, arthritis, heart disease, and neurodegeneration.   The method according to any one of claims 371 to 373, wherein the method is used as a preventive measure against physiological changes caused by aging.

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