WO2006130471A1 - Utilisation d'agonistes et/ ou d'agonistes inverses de recepteurs opioides pour l'inhibition de la consommation de substances psychoactives - Google Patents

Utilisation d'agonistes et/ ou d'agonistes inverses de recepteurs opioides pour l'inhibition de la consommation de substances psychoactives Download PDF

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WO2006130471A1
WO2006130471A1 PCT/US2006/020465 US2006020465W WO2006130471A1 WO 2006130471 A1 WO2006130471 A1 WO 2006130471A1 US 2006020465 W US2006020465 W US 2006020465W WO 2006130471 A1 WO2006130471 A1 WO 2006130471A1
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agent
abuse
delta opioid
sori
substance
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PCT/US2006/020465
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English (en)
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Selena Bartlett
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The Regents Of The University Of California
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms

Definitions

  • This invention pertains to the field of addiction. Particular compounds are identified that inhibit consumption of substances of abuse (e.g., ethanol).
  • substances of abuse e.g., ethanol
  • Alcoholism is the most common form of drug abuse and a major public health problem worldwide. Nevertheless, few drugs exist that modify alcohol intake and the genetic factors that influence alcohol's effects on brain and behavioral processes remain largely uncharacterized. Thus, there is a need for diagnostic tests that can identify individuals with a predisposition to becoming alcoholics and a need for treatments that can alter alcohol consumption.
  • This invention pertains to the discovery that agents with particular agonistic activities on opioid receptors can be administered to a mammal (e.g., a human) to inhibit one or more behaviors associated with chronic consumption of a substance of abuse, and/or cessation of such chronic consumption and/or withdrawal.
  • a mammal e.g., a human
  • a first class of agents that are agonists at mu and delta opioid receptors when they are expressed alone or when the mu and delta opioid receptors are expressed together in cell lines (e.g., SoRI 20144) decrease consumption of a substance of abuse (e.g., alcohol) and also induce/promote weight loss.
  • a substance of abuse e.g., alcohol
  • this invention provides a method of mitigating one or more components of addictive behavior associated with chronic consumption of a substance of abuse, and/or withdrawal therefrom, and/or cessation of consumption of a substance of abuse by a mammal (e.g., a human).
  • the method typically involves administering to the mammal: a first agent that is an agonist at mu and delta opioid receptors when they are expressed alone or when the mu and delta opioid receptors are expressed together in cell lines; and/or a second agent that is an agonist only when the mu and delta opioid receptors are expressed together but not when they are expressed alone.
  • the first agent and said second agent are not naloxone and/or a naloxone derivative.
  • the second agent is an inverse agonist at delta opioid receptors when these receptors are expressed alone.
  • the first agent or the second agent is selected from the group consisting of SNC 80 [(+)-4-[(alphaR)- alpha-((2S,5R)-4-Allyl-2,5-dimethyl-l- ⁇ iperazinyl)-3-methoxybenzyl]-N,N- diethylbenzamide], TIPP, Dmt-Tic-OH, N,N(CH3)2-Dmt-Tic-NH 2 , Tan67, [D-Pen(2,5)]- enkephalin, DPDPE, H-Try-d-Ala-Phe-Glu- VaI-GIy-NH 2 , Deltorphin II, BUBU, deltorphin I, [D-Met 2 ] -deltorphin, 3,4-dimethyl-4-(3-hydroxyphenyl)piperidines derivatives (i.e.
  • the first agent or second agent is selected from the agents of any one of Tables 1 through 5.
  • the first agent and/or second agent is administered in conjunction with a delta opioid receptor antagonist.
  • the agent(s) can be formulated with a pharmacologically acceptable excipient and/or provided as a unit dosage formulation.
  • the substance of abuse is ethanol, an opiate, a cannabinoid, nicotine, or a stimulant.
  • the substance of abuse is morphine, heroin, marijuana, hashish, cocaine, or an amphetamine.
  • the substance of abuse is ethanol.
  • Various components of "addictive" behavior that can be mitigated by the methods of this invention include chronic self-administration of a substance of abuse, craving for the substance of abuse, reinstatement of seeking behavior for the substance of abuse.
  • the methods can be applied to a subject engaging in chronic consumption of a substance of abuse and/or to a subject that has ceased chronic consumption of a substance of abuse, and/or to a subject undergoing one or more symptoms of withdrawal.
  • the methods comprise reducing self-administration of alcohol.
  • the first agent comprises SoRI 20144 and/or a derivative thereof and the second agent comprises SoRI 9409 and/or a derivative thereof.
  • the kits typically comprise a container containing one or more first agent(s) and/or one or more second agent(s) as described herein.
  • the agents can be in separate containers, in the same container, and or formulated as a combined single formulation.
  • the kit additionally comprises a delta opioid receptor antagonist.
  • the agent(s) can be formulated with a pharmacologically acceptable excipient and/or in a unit dosage formulation.
  • kits optionally, additionally comprise instructional materials teaching the use of the agent(s) for the treatment of substance abuse (e.g., to inhibit consumption of alcohol) and/or to induce and/or promote weight loss.
  • the kits comprise SoRI 20144 and/or a derivative thereof and/or SoRI 9409 and/or a derivative thereof.
  • the method typically involves screening a test agent for a first agonist activity at mu and delta opioid receptors when they are expressed alone or when the mu and delta opioid receptors are expressed together in cell lines; and/or a second agonist activity only when the mu and delta opioid receptors are expressed together but not when they are expressed alone; and where agents that show said first agonist activity and/or said second agonist activity are putative agents for inhibiting consumption of alcohol and/or for promoting/inducing weight loss.
  • the agents have inverse agonist activity at the delta opioid receptor when these receptors are expressed alone.
  • the method comprises screening cells that are transfected to express a heterologous mu opioid receptor and/or a heterologous delta opioid receptor.
  • the method comprises measuring phosphorylation of the receptor and/or c AMP levels.
  • this invention also pertains to the discovery that delta opioid receptor antagonists can delay the development of tolerance to the antinociceptive effect of an opiate analgesic. Accordingly, this invention also provides a method of delay the development of tolerance to the antinociceptive effect of an opiate analgesic where the method involves administering a delta opioid receptor antagonist in conjunction with the opiate analgesic.
  • the opiate analgesic is selected from the group consisting of a natural opium alkaloid, a phenylpiperidine derivative, a diphenylpropylamine derivative, a benzomorphan derivative, an oripvaine derivative, and a morphinan derivative.
  • the opiate analgesic is selected from the group consisting of morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, papaveretum, codeine, ketobemidone, pethidine, fentanyl, dextromoramide, piritramide, dextropropoxyphene, bezitramide, dextropropoxyphene, pentazocine, phenazocine, buprenorphine, butorphanol, nalbufine, tilidine, tramadol, and dezocine.
  • Suitable delta opioid receptor antagonists include, but are not limited to 3,4-dimethyl-4-(3-hydroxyphenyl) ⁇ iperidine derivative ⁇ i.e. LY515300 and its derivatives), H-Tyr-TicPsi[CH2N]Cha-Phe-OH, (TICP(Psi)), 2',6'-dimethyltyrosine- l,2,3,4-tetrahydroquinoline-3-carboxylate (Dmt-Tic) peptides, ICI-174,864, SoRI 9409, LY255525, 6 beta naltrexol, naltrexamide, and the like.
  • the delta opioid receptor antagonist can be administered prior to, simultaneously with, or after the opiate analgesic.
  • the delta opioid receptor antagonist and the opiate analgesic are provided as a single unit dosage formulation.
  • a pharmaceutical composition comprising a delta opioid receptor antagonist and an opiate analgesic.
  • the opiate analgesic includes, but is not limited to, a natural opium alkaloid, a phenylpiperidine derivative, a diphenylpropylamine derivative, a benzomorphan derivative, an oripvaine derivative, and a morphinan derivative. .
  • the opiate analgesic includes, but is not limited to, morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, papaveretum, codeine, ketobemidone, pethidine, fentanyl, dextromoramide, piritramide, dextropropoxyphene, bezitramide, dextropropoxyphene, pentazocine, phenazocine, buprenorphine, butorphanol, nalbufine, tilidine, tramadol, dezocine, and the like.
  • Suitable delta opioid receptor antagonists include, but are not limited to 3,4-dimethyl- 4-(3-hydroxyphenyl)piperidine derivative (i.e. LY515300 and its derivatives), H-Tyr- TicPsi[CH2N]Cha-Phe-OH, (T ⁇ CP(Psi)), 2',6'-dimethyltyrosine-l ,2,3,4- tetrahydroquinoline-3-carboxylate (Dmt-Tic) peptides, ICI- 174,864, SoRI 9409, LY255525, 6 beta naltrexol, and naltrexamide.
  • the composition is formulated as a unit dosage formulation.
  • Suitable formulation include, but are not limited to a transdermal formulation, a sustained release formulation, and oral formulation, an injectable formulation, and the like.
  • this invention also provides a method of mitigating psychological or physical dependence on a substance of abuse by a mammal.
  • the method typically involves administering to the mammal a delta opioid receptor antagonist in an amount sufficient to mitigate psychological or physical dependence on the substance of abuse.
  • the substance of abuse is an agent such as ethanol, an opiate, a cannabinoid, nicotine, a stimulant, and the like.
  • the substance of abuse is an agent such as morphine, heroin, marijuana, hashish, cocaine, amphetamines, and the like.
  • the substance of abuse is alcohol.
  • Suitable delta opioid receptor antagonist include, for example, those listed above.
  • the delta opioid receptor antagonist is selected from the group consisting SoRI 9409, LY255525, 6 beta naltrexol, and naltrexamide.
  • the mammal is a mammal engaging in chronic consumption of a substance of abuse.
  • the mammal is a mammal that has ceased chronic consumption of a substance of abuse.
  • the mammal is a human.
  • the human is a human enrolled in a 12-step program.
  • the term "substance of abuse” typically refers to a substance that is psychoactive and that induces tolerance and/or addiction.
  • Substances of abuse include, but are not limited to stimulants (e.g., cocaine, amphetamines), opiates (e.g., morphine, heroin), cannabinoids (e.g., marijuana, hashish), nicotine, alcohol, substances that mediate agonist activity at the dopamine D2 receptor, and the like.
  • Substances of abuse include, but are not limited to addictive drugs. In the case of addictive over-consumption, food, sugar, and the like can be considered a substance of abuse.
  • ethanol is referred to as a substance of abuse it is intended to include ethanol itself as well as a food or drink containing ethanol.
  • the phrase "in conjunction with” when used in reference to the use of one or more agents as described herein indicates that the two agents are administered so that there is at least some chronological overlap in their physiological activity on the organism.
  • the two agents can be administered simultaneously and/or sequentially. In sequential administration there may even be some substantial delay (e.g., minutes or even hours or days) before administration of the second agent as long as the first administered agent has exerted some physiological alteration on the organism when the second administered agent is administered or becomes active in the organism.
  • treat when used with reference to treating, e.g., a pathology or disease refers to the mitigation and/or elimination of one or more symptoms of that pathology or disease, and/or a reduction in the rate of onset or severity of one or more symptoms of that pathology or disease, and/or the prevention of that pathology or disease.
  • inverse agonist refers to a substance that inhibits constitutive activity of the receptor, suggesting that this substance is not technically an antagonist but an agonist with a negative intrinsic activity.
  • a “delta opioid receptor antagonist” is an agent that shows antagonistic activity at the delta opioid receptor.
  • a “preferential delta opioid receptor antagonist” is an agent that shows greater antagonistic activity at a delta opioid receptor than at other opioid receptors.
  • a “specific delta opioid receptor antagonist” is an agent that shows at least 2- fold, preferably at last 5-fold, more preferably at least 10-fold, 20-fold, or 50-fold, and most preferably at least 100-fold, 500-fold, or 1000-fold greater antagonistic activity at a delta opioid receptor than at other opioid receptors.
  • Figure 1 illustrates the structures of morphine, naltrexone, naltrindole, and
  • Figure 5 shows the results for morphine tolerance development in rats. Mean
  • Figure 6 shows the effects of Naltrexone (1 mg/kg) after a period of extinction.
  • Figure 7 shows the effect of SoRI 9409 (5 mg/kg) after a period of extinction.
  • SoRI 9409 ⁇ -opioid receptor antagonist
  • FR3 daily operant self administration session
  • Figure 8 shows the effect of naltrexone (lmg/kg) after a period of home cage deprivation.
  • Figure 9 shows the effect of SoRI 9409 (5mg/kg) after a period of home cage deprivation.
  • SoRI 9409 ⁇ -opioid receptor antagonist
  • FR3 daily operant self administration session
  • This invention pertains to the discovery that agents with particular agonistic activities on opioid receptors can be administered to a mammal (e.g., a human) to inhibit one or more behaviors associated with chronic consumption of a substance of abuse, and/or cessation of such chronic consumption and/or withdrawal.
  • a mammal e.g., a human
  • a first class of agents that are agonists at mu and delta opioid receptors when they are expressed alone or when the mu and delta opioid receptors are expressed together in cell lines e.g., SoRI 20144
  • decrease consumption of a substance of abuse e.g., alcohol
  • a substance of abuse e.g., alcohol
  • this invention provides methods of mitigating one or more components of addictive behavior associated with chronic consumption of a substance of abuse, and/or cessation of such consumption, and/or withdrawal therefrom, by a mammal (e.g., a human) where the method involves administering to the mammal one or of the first and/or second class of agents in an amount sufficient to ameliorate one or more components of addictive behavior (e.g., craving, seeking behavior, anxiety, chronic self- administration, etc.).
  • the agent(s) are not naloxone and/or a naloxone derivitave and/or naltrexone and/or a naltrexone derivative.
  • this invention pertains to the discovery that delta opioid receptor antagonists can delay the development of tolerance to the antinociceptive effect of an opiate analgesic.
  • this invention provides methods of inhibiting the development of such tolerance. The methods typically involve administering a delta opioid receptor antagonist in conjunction with the opiate analgesic.
  • this invention provides pharmaceutical compositions comprising a delta opioid receptor antagonist and an opiate analgesic.
  • delta opioid receptors are implicated in dependence on a substance of abuse, thus inhibition of such receptors can mitigate psychological or physical dependence on said substance of abuse.
  • agents described herein can be effective in the treatment of addictive behaviors (addiction) to any of a wide variety of addictive substances (e.g., substances of abuse).
  • addictive substances e.g., substances of abuse.
  • addictive substances include, but are not limited to stimulants (e.g., cocaine, amphetamines), opiates (e.g., morphine, heroin), cannabinoids (e.g., marijuana, hashish), nicotine, alcohol, substances that mediate agonist activity at the dopamine D2 receptor, and the like.
  • food and/or sugar can be regarded as a substance of abuse (e.g., in compulsive eating disorders).
  • one or more of the agents described herein will be administered to a mammal, more typically to a human to ameliorate one or more behaviors associated with addiction to a substance of abuse (e.g., dependence, craving, self administration, reinstatement, etc.)). Most typically, the agent(s) will be administered to reduce self administration and/or seeking behavior and/or to reduce cravings and/or anxiety, especially for alcohol and/or other substances of abuse. In certain embodiments, the subjects will be subjects that are not being treated for Parkinson's syndrome or other neurological disorders (other than those associated with addictive behavior).
  • the agent(s) are administered to reduce or prevent consumption of the substance of abuse (e.g. , alcohol) and/or to reduce cravings for the substance of abuse.
  • the substance of abuse e.g. , alcohol
  • active agents [0041] It was surprising discovery that various active agents described herein are effective to mitigate/inhibit one ore more or more components of addictive behavior associated with chronic consumption of a substance of abuse. In certain embodiments the agents inhibit consumption/self administration of alcohol and/or other substances of abuse.
  • the agents include compounds that are agonists at mu and delta opioid receptors when they are expressed alone or when the mu and delta opioid receptors are expressed together in cell lines; and/or agonists only when the mu and delta opioid receptors are expressed together but not when they are expressed alone.
  • the agent(s) are inverse agonists at delta opioid receptors when these receptors are expressed alone.
  • a wide variety of agents can be used in the methods of this invention.
  • the agents include, various pyridomorphinans. A number of suitable pyridomorphinans are described in U.S. Patent 6,465,479 (which is incorporated herein by reference in its entirety and particularly for the structures disclosed therein) and can be represented by Formula I:
  • each of Y, X and R is individually selected from the group consisting of hydrogen, hydroxy, alkyl, alkoxy, aryl, halo, CF 3 and NO 2 , provided that at least one of Y, X and R is other than hydrogen; and pharmaceutically acceptable salts thereof.
  • the alkyl groups typically contain 1 to about 6 carbon atoms, and more typically 1 to about 3 carbon atoms, and can be straight, branched-chain or cyclic saturated aliphatic hydrocarbon groups. Examples of suitable alkyl groups include methyl, ethyl and propyl. Examples of branched alkyl groups include isopropyl and t-butyl.
  • Suitable cyclic aliphatic groups typically contain 3-6 carbon atoms and include cyclopentyl and cyclohexyl.
  • Suitable alkoxy groups preferably contain 1-6 carbon atoms and include methoxy, ethoxy, propoxy and butoxy.
  • Examples of aryl groups include phenyl and naphthyl.
  • Examples of halo groups include F, Cl, Br and I.
  • Suitable pyridomorphinans include those possessing an aryl or heteroaryl substituent at the 5 '-position of the pyridine ring of 17-cyclopropylmethyl-4,5 alpha- epoxypyrido[2',3':6,7]morphinan ⁇ see, e.g., Ananthan et al. (2003) Bioorg. Med. Chem., 11(18): 4143-4154, and Ananthan et al. (2003) Bioorg. Med. Chem. Letts., 13: 529-532).
  • Such compounds include pyridomorphinans according to Formula I having combinations of R, X, and Y groups as shown in Table 2.
  • Such compounds also include pyridomorphinans according to Formula II having R 1 groups as show in Table 3.
  • Additional suitable agents include naltrindole derivatives according to
  • R is CPM, allyl, or Me
  • X is H or OH. Certain preferred embodiments are illustrated by combinations of R and X as shown in Table 4.
  • Still other suitable agents include but are not limited to, analogues of the delta opioid receptor antagonist naltrindole possessing a phenyl, phenoxy, or benzyloxy group at the 4'-, 5'-, &-, or 7'-positions and a 2-(2-pyridinyl)ethenyl group at the 5'-position on the indolic benzene ring ⁇ see, e.g., compounds 4-16 in Ananthan et al. (1998) J. Med.
  • the inverse agonist or antagonist is SoRI
  • 9409 (5'-(4-chlorophenyl)-17-(cyclopropylmethyl)-6,7-didehydro-3,14-dihydroxy-4,5alpha- epoxypyrido-[2',3':6,7]morphinan), shown in Figure 1, a naltrexone-derived non-peptide ligand and/or SoRI 20411, and/or the Eli Lilly compound LY255525, and/or its related analogs, 6 beta naltrexol, and/or naltrexamide.
  • the agents include compounds shown in U.S.
  • delta opioid receptor antagonists are disclosed in U.S.
  • Patents 5,578,725; 5,464,841; 5,352,680; 5,332,818; and 4,816,586, which are incorporated herein by reference in their entirety and particularly for the structures disclosed therein.
  • the methods of this invention utilize agents that are agonists at mu and delta opioid receptors when they are expressed alone or when the mu and delta opioid receptors are expressed together in cell lines; and/or that are agonists at the mu and/or delta opioid receptor(s) only when the mu and delta opioid receptors are expressed together but not when they are expressed alone.
  • the agent(s) are also inverse agonists and/or antagonists at delta opioid receptors when these receptors are expressed alone.
  • test materials ⁇ e.g., drugs
  • agonist activity at mu and/or delta opioid receptors and/or for inverse agonist activity at the delta opioid receptors when the receptors are expressed together or alone.
  • Means of screening for agonistic activity or inverse agonistic activity and mu and/or delta opioid receptors are well known to those of skill in the art.
  • such screening is performed by providing cells expressing one or both (mu and/or delta) opioid receptors, contacting the cells with the test agent(s) in the absence and/or presence of a ligand for the receptor(s) ⁇ e.g. 4 a synthetic or endogenous ligand) and determining if the test agent(s) show agonistic or inverse agonistic activity, e.g., by measuring activation and/or inhibition of endogenous (constitutive) activity of the receptor(s).
  • the cells are transfected with one or more nucleic acid constructs that express the desired receptors so that the cell expresses or overexpresses the heterologous mu and/or delta opioid receptor.
  • GPCRs G-protein- coupled receptors
  • Typical assays measure phosphorylation of the receptor and/or other proteins in the pathway, and/or activation of G protein-coupled receptor kinases (GRK), and/or levels of second messenger(s) (e.g., cAMP).
  • GRK G protein-coupled receptor kinases
  • cAMP second messenger(s)
  • kits for performing such assays are commercially available (see, e.g., cAMP assay kit available from NEN Life Science Products Boston, Mass.). It is noted for example, that cAMP assays are described in U.S.
  • delta opioid receptor antagonists of this invention are administered, e.g., to an individual engaged in chronic consumption of a substance of abuse and/or to an individual in withdrawal from chronic consumption of a substance of abuse, and/or to an individual that has ceased or substantially ceased chronic consumption of a substance of abuse.
  • agent or combination of agents described herein will reduce self administration of the substance of abuse and/or craving for such substance, and/or associated anxiety, and/or reinstatement of seeking behavior.
  • the active agent(s) can be administered in the "native" form or, if desired, in the form of salts, esters, amides, prodrugs, derivatives, and the like, provided the salt, ester, amide, prodrug or derivative is suitable pharmacologically, i.e., effective in the present method.
  • Salts, esters, amides, prodrugs and other derivatives of the active agents can be prepared using standard procedures known to those skilled in the art of synthetic organic chemistry and described, for example, by March (1992) Advanced Organic Chemistry; Reactions, Mechanisms and Structure, 4th Ed. N. Y. Wiley-Interscience.
  • Pharmaceutically acceptable salts of the compounds of the present invention include those derived from pharmaceutically acceptable, inorganic and organic acids and bases.
  • suitable acids include hydrochloric, hydrobromic, sulfuric, nitric, perchloric, fumaric, maleic, phosphoric, glycolic, lactic, salicyclic, succinic, toluene-p- sulfonic, tartaric, acetic, citric, methanesulfonic, formic, benzoic, malonic, naphthalene-2- sulfonic, trifluoroacetic and benzenesulfonic acids.
  • Salts derived from appropriate bases include, but are not limited to alkali such as sodium and ammonium.
  • acid addition salts are prepared from the free base using conventional methodology, that typically involves reaction with a suitable acid.
  • a suitable acid such as methanol or ethanol
  • the base form of the drug is dissolved in a polar organic solvent such as methanol or ethanol and the acid is added thereto.
  • the resulting salt either precipitates or can be brought out of solution by addition of a less polar solvent.
  • Suitable acids for preparing acid addition salts include both organic acids, e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like, as well as inorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like.
  • organic acids e.g., acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic
  • An acid addition salt may be reconverted to the free base by treatment with a suitable base.
  • Particularly preferred acid addition salts of the active agents herein are halide salts, such as may be prepared using hydrochloric or hydrobromic acids.
  • preparation of basic salts of the active agents of this invention are prepared in a similar manner using a pharmaceutically acceptable base such as sodium hydroxide, potassium hydroxide, ammonium hydroxide, calcium hydroxide, trimethylamine, or the like.
  • Particularly preferred basic salts include alkali metal salts, e.g., the sodium salt, and copper salts.
  • esters typically involves functionalization of hydroxyl and/or carboxyl groups and/or other reactive groups which may be present within the molecular structure of the drug.
  • the esters are typically acyl-substituted derivatives of free alcohol groups, i.e. , moieties that are derived from carboxylic acids of the formula RCOOH where R is alky, and preferably is lower alkyl.
  • Esters can be reconverted to the free acids, if desired, by using conventional hydrogenolysis or hydrolysis procedures.
  • Amides and prodrugs can also be prepared using techniques known to those skilled in the art or described in the pertinent literature.
  • amides may be prepared from esters, using suitable amine reactants, or they may be prepared from an anhydride or an acid chloride by reaction with ammonia or a lower alkyl amine.
  • Prodrugs are typically prepared by covalent attachment of a moiety that results in a compound that is therapeutically inactive until modified by an individual's metabolic system.
  • the active agents identified herein are useful for parenteral, topical, oral, nasal (or otherwise inhaled), rectal, or local administration, such as by aerosol or transdermally, for prophylactic and/or therapeutic treatment of one or more of the pathologies/indications described herein (e.g., to mitigate one or more behaviors associated with substance abuse).
  • the pharmaceutical compositions can be administered in a variety of unit dosage forms depending upon the method of administration. Suitable unit dosage forms, include, but are not limited to powders, tablets, pills, capsules, lozenges, suppositories, patches, nasal sprays, injectables, implantable sustained-release formulations, lipid complexes, etc.
  • the active agents of this invention are typically combined with a pharmaceutically acceptable carrier (excipient) to form a pharmacological composition.
  • Pharmaceutically acceptable carriers can contain one or more physiologically acceptable compound(s) that act, for example, to stabilize the composition or to increase or decrease the absorption of the active agent(s).
  • Physiologically acceptable compounds can include, for example, carbohydrates, such as glucose, sucrose, or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins, protection and uptake enhancers such as lipids, compositions that reduce the clearance or hydrolysis of the active agents, or excipients or other stabilizers and/or buffers.
  • physiologically acceptable compounds include wetting agents, emulsifying agents, dispersing agents or preservatives that are particularly useful for preventing the growth or action of microorganisms.
  • Various preservatives are well known and include, for example, phenol and ascorbic acid.
  • pharmaceutically acceptable carrier(s) including a physiologically acceptable compound depends, for example, on the route of administration of the active agent(s) and on the particular physio-chemical characteristics of the active agent(s).
  • the excipients are preferably sterile and generally free of undesirable matter.
  • compositions may be sterilized by conventional, well-known sterilization techniques.
  • compositions of this invention are administered to a patient engaged in chronic consumption of a substance of abuse (e.g., alcohol), and/or to a patient suffering from withdrawal from chronic consumption of a substance of abuse, and/or to a patient engaged in maintaining reduced consumption of the substance and/or abstinence in an amount sufficient to prevent and/or cure and/or or at least partially prevent or arrest one or more components of behavior associated with chronic consumption of a substance of abuse or the cessation thereof.
  • a substance of abuse e.g., alcohol
  • An amount adequate to accomplish this is defined as a "therapeutically effective dose.” Amounts effective for this use will depend upon the severity of the disease and the general state of the patient's health.
  • compositions may be administered depending on the dosage and frequency as required and tolerated by the patient.
  • the composition should provide a sufficient quantity of the active agents of the formulations of this invention to effectively treat the condition.
  • concentration of active agent(s) can vary widely, and will be selected primarily based on fluid volumes, viscosities, body weight and the like in accordance with the particular mode of administration selected and the patient's needs. Concentrations, however, will typically be selected to provide dosages ranging from about 0.1 or 1 mg/kg/day to about 50 mg/kg/day and sometimes higher.
  • Typical dosages range from about 3 mg/kg/day to about 3.5 mg/kg/day, preferably from about 3.5 mg/kg/day to about 7.2 mg/kg/day, more preferably from about 7.2 mg/kg/day to about 11.0 mg/kg/day, and most preferably from about 11.0 mg/kg/day to about 15.0 mg/kg/day.
  • dosages range from about 10 mg/kg/day to about 50 mg/kg/day.
  • dosages range from about 20 mg to about 50 mg given orally twice daily. It will be appreciated that such dosages may be varied to optimize a therapeutic regimen in a particular subject or group of subjects.
  • the active agents of this invention are administered orally (e.g., via a tablet) or as an injectable in accordance with standard methods well known to those of skill in the art.
  • the agents may also be delivered through the skin using conventional transdermal drug delivery systems, i.e., transdermal "patches" wherein the active agent(s) are typically contained within a laminated structure that serves as a drug delivery device to be affixed to the skin.
  • the drug composition is typically contained in a layer, or "reservoir,” underlying an upper backing layer.
  • the term “reservoir” in this context refers to a quantity of "active ingredient(s)" that is ultimately available for delivery to the surface of the skin.
  • the “reservoir” may include the active ingredient(s) in an adhesive on a backing layer of the patch, or in any of a variety of different matrix formulations known to those of skill in the art.
  • the patch may contain a single reservoir, or it may contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
  • the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.
  • the backing layer in these laminates which serves as the upper surface of the device, preferably functions as a primary structural element of the "patch" and provides the device with much of its flexibility.
  • the material selected for the backing layer is preferably substantially impermeable to the active agent(s) and any other materials that are present.
  • Other preferred formulations for topical delivery include, but are not limited to, ointments and creams. Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives. Creams containing the selected active agent, are typically viscous liquid or semisolid emulsions, often either oil-in-water or water-in-oil.
  • Cream bases are typically water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also sometimes called the "internal" phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • the specific ointment or cream base to be used is one that will provide for optimum drug delivery. As with other carriers or vehicles, an ointment base should be inert, stable, nonirritating and nonsensitizing.
  • the active agents described herein can be administered orally in which case delivery can be enhanced by the use of protective excipients. This is typically accomplished either by complexing the active agent(s) with a composition to render them resistant to acidic and enzymatic hydrolysis or by packaging the agents in an appropriately resistant carrier, e.g., a liposome.
  • protective excipients e.g., a composition to render them resistant to acidic and enzymatic hydrolysis or by packaging the agents in an appropriately resistant carrier, e.g., a liposome.
  • Means of protecting agents for oral delivery are well known in the art (see, e.g., U.S. Patent 5,391,377).
  • Elevated serum half -life can be maintained by the use of sustained-release "packaging" systems.
  • sustained release systems are well known to those of skill in the art (see, e.g., Tracy (1998) Biotechnol. Prog. 14: 108; Johnson et al (1996), Nature Med. 2: 795; Herbert et al. (1998), Pharmaceut. Res. 15: 357, and the like).
  • one or more components of the solution can be provided as a "concentrate”, e.g., in a storage container (e.g., in a premeasured volume) ready for dilution, or in a soluble capsule ready for addition to a volume of water.
  • one or more active agents described herein are administered alone or in combination with other therapeutics in implantable (e.g., subcutaneous) matrices.
  • a major problem with standard drug dosing is that typical delivery of drugs results in a quick burst of medication at the time of dosing, followed by a rapid loss of the drag from the body. Most of the side effects of a drag occur during the burst phase of its release into the bloodstream. Secondly, the time the drug is in the bloodstream at therapeutic levels is very short, most is used and cleared during the short burst.
  • Drugs e.g., the active agent(s) described herein
  • Drugs embedded, for example, in polymer beads or in polymer wafers have several advantages. First, most systems allow slow release of the drug, thus creating a continuous dosing of the body with small levels of drug. This typically prevents side effects associated with high burst levels of normal injected or pill based drags. Secondly, since these polymers can be made to release over hours to months, the therapeutic span of the drag is markedly increased. Often, by mixing different ratios of the same polymer components, polymers of different degradation rates can be made, allowing remarkable flexibility depending on the agent being used.
  • a long rate of drug release is beneficial for people who might have trouble staying on regular dosage, such as the elderly, but is also an ease of use improvement that everyone can appreciate.
  • Most polymers can be made to degrade and be cleared by the body over time, so they will not remain in the body after the therapeutic interval.
  • polymer based drug delivery Another advantage of polymer based drug delivery is that the polymers often can stabilize or solubilize proteins, peptides, and other large molecules that would otherwise be unusable as medications. Finally, many drag/polymer mixes can be placed directly in the disease area, allowing specific targeting of the medication where it is needed without losing drag to the "first pass" effect. This is certainly effective for treating the brain, which is often deprived of medicines that can't penetrate the blood/brain barrier.
  • sustained release systems include, but are not limited to Re- Gel®, SQ2Gel®, and Oligosphere® by MacroMed, ProLease® and Medisorb® by
  • this invention discloses the administration of delta opioid receptor antagonists (more preferably a preferential- and still more preferably a specific delta opioid receptor antagonist) in conjunction with one or more opiate analgesics to delay the development of tolerance to the antinociceptive effect of the opiate analgesic(s).
  • the opiate analgesic(s) are and delta opioid receptor antagonist(s) are provided as combined formulation.
  • the receptor antagonist(s) and analgesic(s) can be combined at the time of administration or they can be provided as a single formulation.
  • Suitable delta opioid receptor antagonists include, but are not limted to those described above.
  • Suitable opiate analgesics include, but are not limited to natural opium alkaloids ⁇ e.g., morphine, opium, hydromorphone, nicomorphine, oxycodone, dihydrocodeine, diamorphine, papaveretum, codeine, and the like), phenylpiperidine derivatives ⁇ e.g., ketobemidone, pethidine, fentanyl, and the like), diphenylpropylamine derivatives ⁇ e.g., dextromor amide, piritramide, dextropropoxyphene, bezitramide, dextropropoxyphene, and the like), benzomorphan derivatives ⁇ e.g., pentazocine, phenazocine, and the like), oripvaine derivatives ⁇ e.g., buprenorphine, and the like), morphinan derivatives ⁇ e
  • kits for practice of the methods of this invention typically include a container containing one or more active agents as described herein.
  • the kits typically additionally include instructional materials teaching the use of such agent to inhibit one or more components of addictive behavior associated with consumption of a substance of abuse ⁇ e.g., to inhibit consumption of alcohol).
  • the instructional materials can teach preferred dosages, modes of administration, counter- indications, and the like.
  • While the instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention.
  • Such media include, but are not limited to electronic storage media ⁇ e.g., magnetic discs, tapes, cartridges, chips), optical media ⁇ e.g., CD ROM), and the like.
  • Such media may include addresses to
  • sucrose concentration was gradually decreased ⁇ i.e. 5, 2, and finally 0%).
  • the animals had continuous access to 10% v/v ethanol solution and a separate water bottle. Intake was measured twice daily, 16 and 24 hrs. after fresh fluids were placed on the cages. Measurements were taken to the nearest .5 ml. The data was corrected for evaporation and spillage by subtracting the mean fluid loss measured in two drinking tubes placed on an empty cage. Position of the tubes (left/right) was alternated to control for side preferences. Drug administrations began after the rats had reached stable drinking levels of the 10% v/v ethanol solution (2-3 weeks following removal of the sucrose).
  • each rat was tested at each dose of SoRI 9409 and SoRI20411 were delivered intraperitoneally (ip) with a minimum of four days between drug administrations to allow for the drugs to washout. Animal weights were measured daily in order to calculate the gram per kilogram intake. Ethanol preference (%) was calculated as the mis. of ethanol consumed divided by the total fluid consumption (mis. of EtOH + mis. of water).
  • SoRI9409 and SoRI20411 were supplied by the Southern Research Institute.
  • the drugs were initially dissolved DMSO and then further diluted with distilled water (injection volume of lmL/kg for all doses). 5-10 ⁇ L of glacial acetic acid was added to keep the drugs in solution.
  • MOPr delta opioid receptor
  • DOPr delta opioid receptor
  • N-terminal FLAG- and/or HA-tagged MOPr or DOPr constructs were stably expressed in HEK293 cells.
  • DMEM Gibco BRL
  • Fetal Bovine Serum Fetal Bovine Serum
  • N-terminal FLAG- and/or HA-tagged MOPr or DOPr constructs were stably expressed in HEK293 cells.
  • single colonies were chosen and propagated in the presence of selection-containing media.
  • the antibody- feeding immunocytochemistry were essentially as described 5 except DAMGO (DAMGO, 5 ⁇ M, 30 min), SORI9409 (5 ⁇ M), or SoRI 20411 (5 ⁇ M) were used. Briefly, cells stably expressing FLAG-tagged MOPr or DOPr were grown on coverslips to 50% confluency.
  • Live cells were fed either Ml or HA antibody (Sigma) directed against the FLAG tag (1 : 1000, 30 minutes or HA tag (1 : 1000, 30 mins). Cells were then treated with drug (5 ⁇ M DA, 30 minutes) or left untreated. Untreated cells were then fixed with 4% formaldehyde in PBS. Cells were then either fixed and the cells permeabilized in blotto with 0.1% Triton X- 100 and stained with fluorescently conjugated secondary antibody (1:500, Molecular Probes).
  • opioid antagonists such as the non-selective opioid antagonist, naltrexone
  • This opioid combination has reportedly provided greater levels of pain relief and reduced morphine tolerance in chronic pain patients (Gan et al. (1997) Anesthesiology, 87: 1075-1081).
  • naltrexone may selectively block sustained activation of excitatory opioid receptor functions such as those postulated to mediate tolerance and dependence, while minimizing antagonist activity at inhibitory opioid receptors that mediate antinociception (Crain and Shen (1995) Proc. Natl. Acad. ScL, USA, 92(7): 10540-10544; Shen and Crain (1997) Brain Res. 757: 176-190; Wang et al. (2005) Neuroscience, 135: 247-261).
  • Previous studies in mice have indicated that the ⁇ -opioid receptor may be involved in the development of tolerance to the effects of ⁇ -opioid agonists, such as morphine (Abdelhamid et al.
  • mice with a genetic deletion of the cloned ⁇ -opioid receptor were reported not to develop antinociceptive tolerance to morphine, in contrast to wild-type mice (Zhu et al. (1999) Neuron, 24: 243-252).
  • %MPE post-drug latency - predrug latency x 100% maximum latency (9 s) - predrug latency
  • Rats administered twice daily doses of morphine were shown to be tolerant to the antinociceptive effects of morphine after 48-54 h ( Figure 5).
  • a delayed tolerance to the antinociceptive effects of morphine in rats coadministered morphine with either naltrexone or SoRI 9409 (10 ng/kg) was observed (72-84 h).
  • rats co-administered SoRI 9409 with morphine displayed slightly higher levels of antinociception than rats administered morphine with naltrexone at the 24 to 48 h post-dosing time-points, these were not significant different (p > 0.05).
  • Rats administered either naltrexone or SoRI 9409 alone produced insignificant levels of antinociception, compared to pre-dosing baseline latencies (p > 0.05).
  • Naltrexone has been shown to be effective in treating alcoholism it has a range of adverse side effects and subsequent poor compliance levels. The adverse effects may be attributed to the non-specific nature of the compound and so a number of derivatives with increased specificity for individual opioid receptor subtypes have been developed, although without specific testing, their efficacy in is unpredictable.
  • the present study pertains to the investigation of the effects of SoRI 9409 in a beer/near beer operant self administration model and to the determination of whether or not ⁇ -opioid receptor antagonism produces a similar or more specific treatment profile compared to Naltrexone.
  • Rats were randomly assigned to one of four groups and pre-exposed to their assigned reinforcer solutions (4.5% beer (v/v), near beer, 5% sucrose (g/v), or 4.5% ethanol (v/v)) in the home cage for 3 days before commencing operant sessions.
  • Operant sessions were conducted in standard operant behavior chambers (Coulbourn Instruments Inc.) that include 2 levers, a liquid delivery system, tone, stimulus lights above each lever and a house light. Sessions were conducted 5 days a week (Mon - Fri) at the same time each day. Rats were trained to respond for a liquid reinforcer by first water depriving them for 22 hours and then placing them in the operant chambers over night for 12-14 hours for up to 2 sessions.
  • the reinforcer solution was available after successful completion of an operant (active lever press) response on a fixed ratio FRl schedule; 1 lever press on the active lever results in the light above the active lever being turned on and a tone sounding for 3 seconds, followed by delivery of 1 reward of 0.1ml reinforcer in the drinking port.
  • an operant active lever press
  • 1 lever press on the active lever results in the light above the active lever being turned on and a tone sounding for 3 seconds, followed by delivery of 1 reward of 0.1ml reinforcer in the drinking port.
  • animals were placed on restricted water for 1 hour per day in the home cage, immediately after completing an operant session, for 2-3 days. Rats were trained to respond for reinforcers without using a sucrose fading technique.
  • rats were placed in the operant chambers for 45 minute sessions on an FRl schedule, over the course of two weeks animals progressed to having Ad Lib water access in the home cage and continued 45 minutes sessions FRl, for a further 3-4 sessions and then on to an FR3 schedule for 30 minute sessions (FR3 requires 3 consecutive presses on the active lever for presentation of cues and reward delivery). AU future sessions were 30 minutes on an FR3 schedule of reinforcement. Animals were trained until they reached a stable baseline of responding on the active lever, which took 5 weeks (25 sessions).
  • Rats administered with lmg/kg Naltrexone showed significant reduction in responding for all reinforcers after a period of extinction (Figure 6).
  • rats administered with 5m/kg SoRI 9409 showed significant reduction of responding only for near beer and 4.5% ethanol. Sucrose responding was unaffected and although beer responding showed a trend towards reduction it was not significant ( Figure 7).
  • Figures 8 and 9 In contrast to animals going through extinction training animals who were home cage deprived showed a much more significant beer-selective response to both Naltrexone and SoRI 9409 ( Figures 8 and 9). This indicates that SORI9409 is more effective for use in alcohol deprivation.

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Abstract

La présente invention a trait à des composés et des procédés d'inhibition d'un ou de plusieurs composantes de comportement associées à des substances psychoactives. Dans certains modes de réalisation, il a été démontré que des composés SoRI9409 et SoRI20411 sont inhibiteurs de la consommation d'une substance psychoactive (par exemple, l'éthanol).
PCT/US2006/020465 2005-05-27 2006-05-26 Utilisation d'agonistes et/ ou d'agonistes inverses de recepteurs opioides pour l'inhibition de la consommation de substances psychoactives WO2006130471A1 (fr)

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US7541364B2 (en) 2003-08-27 2009-06-02 Southern Research Institute Pyridomorphinans, pyridazinomorphinans and use thereof
US8846104B2 (en) 2006-06-19 2014-09-30 Alpharma Pharmaceuticals Llc Pharmaceutical compositions for the deterrence and/or prevention of abuse
JP2015515986A (ja) * 2012-05-02 2015-06-04 サザン リサーチ インスティテュート 複素環式縮合モルフィナン類、その使用及びその製造方法

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US6465479B1 (en) * 1999-08-13 2002-10-15 Southern Research Institute Pyridomorphinans and use thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6465479B1 (en) * 1999-08-13 2002-10-15 Southern Research Institute Pyridomorphinans and use thereof

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7541364B2 (en) 2003-08-27 2009-06-02 Southern Research Institute Pyridomorphinans, pyridazinomorphinans and use thereof
US7951817B2 (en) 2003-08-27 2011-05-31 The United States Of America As Represented By The Department Of Health And Human Services Pyridomorphinans, pyridazinomorphinans and use thereof
US8846104B2 (en) 2006-06-19 2014-09-30 Alpharma Pharmaceuticals Llc Pharmaceutical compositions for the deterrence and/or prevention of abuse
US8877247B2 (en) 2006-06-19 2014-11-04 Alpharma Pharmaceuticals Llc Abuse-deterrent multi-layer pharmaceutical composition comprising an opioid antagonist and an opioid agonist
JP2015515986A (ja) * 2012-05-02 2015-06-04 サザン リサーチ インスティテュート 複素環式縮合モルフィナン類、その使用及びその製造方法

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