CN101208098A - Amylin and amylin agonists for treating psychiatric diseases and disorders - Google Patents
Amylin and amylin agonists for treating psychiatric diseases and disorders Download PDFInfo
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Abstract
Compositions and methods for preventing, treating or controlling conditions or disorders associated with obesity, diet, and nutrition are provided. The methods provided generally involve the administration of an amylin or an amylin agonist to a subject in order to prevent, treat or controlling conditions or disorders associated with obesity, diet, and nutrition.
Description
The cross reference of related application
The application requires the U.S. temporary patent application number 60/667 of on March 31st, 2005 application, 335, the U.S. temporary patent application of on March 31st, 2005 application number 60/666,681, the U.S. temporary patent application of on April 28th, 2005 application number 60/675, the U.S. temporary patent application of on January 20th, 441 and 2006 application number 60/760,583 is introduced at this full content with every piece and to be used for all purposes.
Technical field
The disclosure is in the field of medicaments, particularly relates to psychology and psychiatry, and the field of health, diet and nutrition.
Background of invention
Psychosis and mental disorder (psychiatric diseases or disorders) (being also referred to as mental illnesses or disorders (psychosis and mental disorder)) are described in the source as the Diagnostic and StatisticalManual of Mental Disorders (psychotic diagnostic and statistical manual) of AmericanPsychiatric Association (APA,American Psychiatric Association) or DSM-IV.The big class of mental disorder includes, but not limited to affective disorder, anxiety neurosis, schizophrenia and other mental disorders, material associated disorders, sleep disorder, somatoform disorder and eating disorders.The example of affective disorder comprises two-phase obstacle and depression.Other situations that fall into the big class of above-mentioned obstacle can find at DSM-IV, are incorporated herein by reference with its integral body at this.These are the weak diseases of making us that influence hundreds of millions crowds, and with regard to treatment, the forfeiture productivity and emotional toll, relate to huge and inestimable expense.
In calendar year 2001, National Institute of Mental Health (the state-run Mental Health institute of the U.S.) has announced the statistics overview of describing Americanism obstacle sickness rate.In this report, estimate in the given time that 22.1% age is that 18 years old and bigger American suffer from diagnosable mental disorder (Reiger etc. (1993) Archives of General Psychiatry 50:85-94).When utilization during to U.S. in 1998 generaI investigation, influenced crowd's quantity is 44.3 hundred ten thousand.
Wherein, depression comprises major depression, dysthymic disorder and two-phase obstacle.About age of 9 to 9.5% suffers from depressive disorder 18 years old or bigger U.S. crowd.The direct cost of having reported depression is about $800 the 2nd/100000003rd, three, is born by commerce.The indirect cost relevant with depression is as the forfeiture productivity, because as " working (presenteeism) reluctantly " situation, more be difficult to calculate, reluctantly working is described in work but crowd limited in one's ability (Durso, Employee Benefit News, in December, 2004) that they produce or participate in.
Another kind of mental illness is an anxiety neurosis.These obstacles comprise panic disorder, obsession, posttraumatic stress disorder, broad sense anxiety neurosis and phobia.About 19.1 hundred million 18 to 54 years old U.S. adult (about 13.3% people in the given time in this age group) suffers from anxiety neurosis.
Another kind of common mental disorder is an eating disorders.There are three kinds of main types, nervous anorexia, bulimia and disease of eating too much at one meal.These are relevant with the idea of feeling about build usually mental illness and irrelevant with actual body weight or body weight index usually.Estimate annual 0.56% the people's apositia mortality rate that has, or about 5.6% per ten year, be higher than 15-24 among total crowd year women because about 12 times of the annual mortality rate (Sullivan (1995) AmericanJournal of Psychiatry 152:1073-1074) of all causes of death.It should be noted that psychosis exists with the key element of other mental disorders usually.
Another kind of mental illness is a schizophrenia.In the given time, surpass 200,000,000 people and be diagnosed as clinically and suffer from schizophrenia, and in about 1% U.S. crowd, have the lifelong sickness rate of this disease.Schizophrenia is chronic, degenerative disorders, and the patient of estimation 75% treatment does not obtain to recover fully.Usually bring the side effect of weight increase and possible diabetes with newer (atypia) antipsychotic drug treatment schizophrenia.
Schizoid exemplary types comprises paranoid schizophrenia.These people suspect that very other people also have very big destruction notion in their behavior root usually.Hallucination, illusion more commonly, be disease main with common part.Suffer from people's speaking incoherently of disorganized schizophrenia (hebephrenictype Split disease) and have the emotion and the emotion of incompatibility situation.Disintegrate the type Split disease and do not have hallucination usually.Catatonic type schizophrenia, wherein the people is very unsociable and eccentric, passive and isolated, and has significant psychomotor disorder.Residual schizophrenia, wherein the people does not suffer from illusion, hallucination or disorderly language and behavior usually, still amotivational and interest in life day by day.Class schizophrenia, wherein the people has the symptom of schizophrenia and affective disorder, as major depression, two-phase is manic or it is manic to mix.Non-type schizophrenia, wherein disease meets schizoid general diagnostic standard, but does not meet above-mentioned any hypotype, or has the feature that surpasses a kind of hypotype and the diagnostic characteristic that does not have the particular series of clear superiority.
Psychosis and mental disorder can be found in any age group.Therefore, can be in young and adult (be defined herein as 65 years old or following those) and baby, child, teenager and old people (be defined herein as surpass 65 years old) these diseases of discovery.In fact, the crowd of specific part may tend to suffer from a kind of disease especially, as the eating disorders among teenager and the youth.The old people is easy to suffer from the such disease of depression especially.
Common treatment comprises psychology and behavior therapy, electric shock treatment and/or medicine.The form of therapy that psychosis is common, or at least one part of treatment are to give medicine.What this area needed is that molecule (1) effectively to present antidepressant (is for example treated, trinucleated, the monoamine oxidase inhibitor, selectivity 5-hydroxy tryptamine reuptake inhibithors) effectively treatment depression of chemical sproof those patients (2), anxiety, schizophrenia or other psychosiss or mental disorder and do not have the adverse side effect of present medicine, (3) having faster, therapeutical effect begins, and/or (4) improvement is present in psychosis such as depression usually, in anxiety and schizophrenia (just the having enumerated some) treatment and make altogether sick (for example, the diabetes of the more difficult health of psychotic treatment, pain, weight increase).
Be incorporated herein by reference with its integral body at these whole lists of references of quoting.
General introduction
One generalized aspect in, the method that provides comprises the purposes that the pancreas opsonin (amylin) for the treatment of effective dose and agonist, analog or derivant are used for the treatment of mental disorder.In specific embodiment, mental disorder is affective disorder, anxiety neurosis, schizophrenia or other mental disorders, material associated disorders, sleep disorder, somatoform disorder and/or eating disorders.In specific embodiment, mental disorder is depression or two-phase obstacle.In specific embodiment, mental disorder is an obsession.In specific embodiment, the method that provides does not comprise the treatment eating disorders.In other embodiments, the method that provides does not comprise the treatment apositia.In specific embodiment, the method that provides does not comprise somatoform disorder.In specific embodiment, pancreas opsonin and agonist thereof, analog or derivant are used for the treatment of the basic spirit disease of eating disorders.In specific embodiment, pancreas opsonin and agonist thereof, analog or derivant are used for the treatment of the basic spirit disease of somatoform disorder.In specific embodiment, amylin agonist does not comprise calcitonin and/or the relevant peptide (CGRP) of calcitonin gene.Still in other embodiments, amylin agonist does not comprise the analog of calcitonin and/or CGRP.
Again on the one hand in, the method that provides comprises that treatment maybe needing to thirst for the patient's that treats neurological disorder, comprise will the treatment effective dose pancreas opsonin, its agonist, analog or derivant deliver medicine to the patient.In specific embodiment, the patient is overweight.In other embodiments, the patient is fat.Still in other embodiments, the patient is thin, does not have overweight or fat.Still in other embodiments, the patient suffers from metabolic disorder.In other embodiments, the patient suffers from diabetes, metabolic syndrome, glucose tolerance attenuating or development of insulin resistance.In other embodiments, pancreas opsonin and agonist thereof, analog or derivant help the patient to change monophagia or food to crave in the ability of (food cravings) be useful.
In aspect another is generalized, comprise the pancreas opsonin of drug treatment effective dose in this method that provides, or its agonist, analog and derivant, in conjunction with being used for psychotic conventional therapy.In specific embodiment, this combination comprises and gives electric shock treatment (ECT).In other embodiments, this combination comprises and gives another kind of psychosis medicine.Still in other embodiments, the psychosis medicine be one or more tricyclics, monoamine oxidase inhibitor (MAOI), selectivity 5-hydroxy tryptamine reuptake inhibithors (SSRI), 5-hydroxy tryptamine and noradrenaline reuptake inhibitor (SNRI), medical herbs antidepressants (for example, St John ' s Wort or Hypericum), or second filial generation antipsychotic drug (SGA).
In aspect another is generalized, comprise the adverse side effect for the treatment of another kind of psychosis medicine, comprise pancreas opsonin, or its agonist, analog and derivant deliver medicine to the patient who needs effective dose in this method that provides.In specific embodiment, other psychosis medicines are second filial generation antipsychotic drug.In specific embodiment, the adverse side effect of other psychosis medicines is weight increase.In other embodiment, the adverse side effect of other psychosis medicines is diabetes.
In aspect another summary, comprise the treatment mental disorder in this method that provides, comprise its chemical compound to the regulating action adjusting behavior path of metabolic pathway or function that passes through of drug treatment effective dose, metabolic pathway or function include but not limited to glucose metabolism, lipid metabolism, protein metabolism and gross energy metabolism.In specific embodiment, the behavior path is thyroliberin-releasing factor (CRF) path of regulating at least a composition of hypothalmus-pituitary-adrenal axis.In one embodiment, the behavior path is the dopamine path.In other embodiments, the behavior path is 5HT
IAPath or any path that comprises the serotonin activation system.In specific embodiment, metabolism or behavior path are that sugar is regulated, any in glucocorticoid responsiveness or the stress response.In specific embodiment, chemical compound is pancreas opsonin or its agonist, analog or derivant.
On the other hand, comprise it regulates the behavior path to the regulating action of food intake the compounds for treating mental disorder of passing through by the drug treatment effective dose in this method that provides.In specific embodiment, chemical compound is pancreas opsonin or its agonist, analog or derivant.
On the other hand, the disclosure provides pancreas opsonin, its agonist, analog or derivant to be used to make the purposes of treatment psychosis described herein and mental disorder medicine.On the other hand, the disclosure provides pancreas opsonin, its agonist, analog or derivant to be used to make for example purposes of second filial generation antipsychotic drug adverse side effect medicine of the another kind of psychosis medicine of treatment.
The accompanying drawing summary
Figure 1A and 1B have described the figure of pancreas opsonin to the stress-induced effect of ingesting.In these figure, R represents to accept the animal of Restraint Stress and the control animal that C represents not accept Restraint Stress.
Fig. 2 has described pancreas opsonin and the contrast agents figure to the hyperthermia effect of stress-induced in the mice.
Fig. 3 has described pancreas opsonin and the contrast agents figure to pellet shot from a slingshot (marble burying) effect of burying.
Fig. 4 has described pancreas opsonin and vehicle Control to accepting the figure of forced swimming test animal effect.
Fig. 5 has described pancreas opsonin and contrast agents to the inhibiting figure of prepulse.
Fig. 6 has described pancreas opsonin and the contrast agents figure to the effect of phencyclidine (PCP) induced movement.
Fig. 7 A and 7B have described the figure of clozapine to the body weight effect.Figure among Fig. 7 A has described clozapine and separately the effect of body weight and the figure among Fig. 7 B has been described the effect to body weight of clozapine and pancreas opsonin compositions.
Detailed Description Of The Invention
Have been found that amylin, amylin agonist, amylin analog, amylin agonist Analog, amylin derivative or its combination can be regulated stress response system and/or CRF and/or sugar The effect of cortin (GC) therefore presents the drug therapy that makes new advances and selects. As demonstrate,proving at this Bright, the amylin administration as if reduce or the protection antagonism stress and impact (for example, anxiety, The change of compulsive behavior, depression, amentia, feed behavior). We have also proved at this, In specific animal behavior test, the amylin administration has caused Behavioral effect, as anti-stress, Antianxiety, antidepression and antipsycholic action.
In exploring new drug therapy, notice various metabolism symptom (for example, diabetes, Obesity) relevant with behavior disorder (for example, PD, schizophrenia). Although It has been generally acknowledged that these diseases are common diseases, but exist up-to-date evidence to show that behavior and metabolism change In many cases be relevant on the physiology (Laugero etc. (2001) Endocrinology 142: 2769-2804; Laugero etc. (2002) Endocrinology 143:4552-4562; Dallman Deng (2003) Proc.Natl.Acad.ScL USA 100:11696-11701; Laugero (2004) Vitamins and Hormanoes, 68 volumes, Litwack (editor)). These surfaces are fully upper Common contact between the different morbid state is that chronic stress and brain CRF and adrenal cortex swash Element, the relevant change of GC.
CRF and GC molecule regulate behavior under normal and the stressed condition, neuroendocrine, In the metabolic function of advocating peace, play a crucial role. The expression of chronic stress and these molecules and activity Induce and behavior disease such as anxiety and depressed height correlation, also with some obesity and diabetes phase Close. Exist evidence CRF and adrenal cortex unusual with metabolic syndrome, the mistake of autoimmunity inflammation Transfer, acute and chronic neurodegenerative, sleep-disorder, chronic ache, eating disorder, chronic Jiao Consider relevant (Wong etc. (2000) the Proc.Natl.Acad.ScL USA with PD of obstacle 97:325-330; Sarnyai etc. (2001) Pharmacol.Rev.53:209-243; Heimichs Deng (1999) Baillieres Best Pract.Res.Clin.Endocrinol.Metah.13:541-554; Chrousos (2000) Int.J.Obes.Relat.Metab.Disoral.24:S50-S55; Peek etc. (1995) Ann.NY.Acad.ScL 771:665-676; Grammatopoulos etc. (1999) Lancet 354:1546-1549; Dallman etc. (2003) Proc.Natl.Acad. ScL USA 100:11696-11701).
As proving at this, amylin in the behavior test, demonstrate have antianxiety, anti-pressing down The feature of strongly fragrant and antipsychotic agent. Therefore, now verified amylin and amylin swash Moving agent has the ability of surprising treatment phrenoblabia. Treatable phrenoblabia comprises The disturbance of emotion, anxiety disorder, schizophrenia and other phrenoblabias, material associated disorders, sleep Dormancy obstacle, somatoform disorder and eating disorder. These compounds have metabolic disorder in treatment The phrenoblabia of key element, eating disorder for example, or suffer from patient or the trouble of phrenoblabia in treatment Spiritedness obstacle and suffer from those of metabolic disorder especially effective.
More particular types of above-mentioned obstacle can find in DSM-IV. Below just pass through The treatable obstacle example of method disclosed herein. Example comprises the disturbance of emotion, can comprise Depression and two-phase obstacle. They can further be characterized by PD, dysthymia barrier Hinder, I type two-phase obstacle, II type two-phase obstacle, circulation mood disease, non-specific two-phase obstacle, Because the disturbance of emotion that medical condition causes, the disturbance of emotion or the non-specific emotion that material is induced Obstacle. Anxiety disorder can comprise panic disorder, special neurosis, social phobia, obsession, Posttraumatic stress disorder, acute stress disorder, GAD, since medical condition cause Anxiety disorder, anxiety disorder and the non-specific anxiety disorder that material is induced.
The material associated disorders comprise anxiety disorder that substance dependence, substance addiction, material are induced and The disturbance of emotion that material is induced. Substance dependence and substance addiction can take place in various materials, bag Draw together but be not limited to, alcohol, nicotine, cocaine, opium, anesthetic, psychedelic, peace are non-He is bright, Phencyclidine, Phencyclidine sample material, inhalant and sedative. Jiao that material is induced Consider disease and can respond material and take place, these materials include but not limited to caffeine, hemp, can Cacaine, psychedelic, amphetamine, Phencyclidine, Phencyclidine sample material and inhalant. Thing The disturbance of emotion that matter is induced can respond material and take place, and these materials include but not limited to and can block Cause, psychedelic, opium, amphetamine, Phencyclidine, Phencyclidine sample material and inhalant. The obstacle that material is induced can respond the combination of a kind of material or material and take place, such as many kinds of substance Relevant obstacle.
In some embodiments, the method that provides comprises drug-induced phrenoblabia or by disease The treatment of the phrenoblabia that sick treatment causes. For example, hedonistic homeostatic Dysregulation is familiar with in the patient who suffers from Parkinsonian experience dopamine replacement therapy The neuropsychic behavior obstacle that arrives. Dopamine replacement therapy among these patients seems the stimulation maincenter The dopaminergic path also causes behavior disorder, has that some are relevant with the excitant habituation similar The property. Giovannoni etc. (2000) J.Neurol.Neurosurg.Psychiatry 68:423-428.
Eating disorders can comprise nervous anorexia, nerve bulimia and non-specific eating disorders.These eating disorders comprise gluttony.In specific embodiment, the method that provides relates to treats the psychosis relevant with eating disorders.In other embodiments, the method that provides does not comprise the treatment of eating disorders.In specific embodiment, the method that provides does not comprise the treatment of apositia.In other embodiments, the method that provides is used for the treatment of the psychosis relevant with the apositia patient.In specific embodiment, the method that provides does not comprise the treatment of gluttony.
In some embodiments, the method that provides can be used for the treatment of the patient who stands intermittent aggressive behavior (IEB).IEB characterizes various obstacles, comprises gluttony, substance abuse, alcoholism, abnormal sexual behavior and compulsive gambling.When once in a while normal behaviour over-conversion become repeatability, IEB takes place when intermittent, unconformable behavior is excessive.Corwin(2006)Appetite?46：11-15。
In specific embodiment, the method that provides does not comprise the treatment of somatoform disorder.In specific embodiment, the method that provides comprises somatoform disorder but does not comprise spiritual treatment of pain.In other embodiments, the method that provides comprises the psychotic treatment relevant with pain.
One generalized aspect in, consider reduce or relax stress or regulate stress path chemical compound can be used as rem.In aspect another is generalized, consider that the chemical compound that can influence or regulate metabolism disorder and spirit or action process can be used as rem.In aspect another is generalized, consider that the chemical compound that can alleviate or reverse metabolism disorder can be as the therapeutic drug treatment of psychosis or mental disorder.The chemical compound that the method that is used for providing is provided can be pancreas opsonin, amylin agonist, pancreas opsonin analog and pancreas opsonin derivant.In specific embodiment, amylin agonist does not comprise calcitonin and/or CGRP.
Proposed such theory: expectation is not only treated psychosis but also is alleviated the sick altogether medicine of disease health and causes treatment response rate and the successful result who improves among the psychotic.Health is altogether sick, as diabetes, aggravated the sickness rate that psychosis causes and caused treating the reduction of replying.Because its anti-diabetic, obesity and appetite inhibiting effect, pancreas opsonin and agonist thereof are particularly useful in method described herein.Pancreas opsonin and agonist thereof can be useful helping the patient to have in the ability that changes monophagia further, be described in the total U.S. patent application No.60/666 of application on March 31st, 2005, the PCT apply for agency of on March 31st, 681 and 2006 application is tried a case among the part catalogue no.0113-PCT-O fully, and separately content is incorporated herein by reference with its integral body.These effects can improve treatment response rate and the successful result of suffering from psychosis and presenting the particular patient group of obesity, fat relevant disease or eating disorders (for example, take food at diabetes, metabolic syndrome, obesity, Cushing's syndrome, hypercortisolism, atypia major depression, schizophrenia, seasonal affective disorder, polycystic ovary syndrome, posttraumatic stress disorder, night syndrome, nerve disease of eating too much at one meal, gluttony eating disorders and chronic fatigue syndrome).In specific embodiments, method does not comprise the treatment of apositia.In other embodiments, method comprises the psychosis that treatment is relevant with apositia.
A generalized aspect comprises natural generation and purposes periphery excretory pancreas opsonin peptide or amylin agonist, analog or derivatives for treatment mental disorder again.In some embodiments, provide the method that is used for patient's mental disorder, wherein this method comprises and will effectively treat the pancreas opsonin of mental disorder content or the patient that amylin agonist, analog or derivant deliver medicine to needs.In certain embodiments, mental disorder is natural or undetermined nosetiology.In some cases, mental disorder is caused by the medicine that is used for or treat various disease.Therefore, in some embodiments, the method of inductive mental disorder of medicine or the mental disorder that causes of treatment patient disease is provided, and wherein this method comprises and will effectively treat the pancreas opsonin of mental disorder content or the patient that amylin agonist, analog or derivant deliver medicine to needs.Because pancreas opsonin peptide is natural excretory hormone, can reduces and accept usually the specified treatment of mental disorder and the side effect feature that the medicine patient exists usually of being used for.Another summary aspect comprises the purposes of the chemical compound that can treat the psychosis that exists among the patient and metabolism disorder.
Pancreas opsonin, amylin agonist, pancreas opsonin analog or pancreas opsonin derivant also may be better than some other antidepressants, anxiety and/or antipsychotic agent, because it does not promote weight increase, in fact, can induce to lose weight.This specific character of pancreas opsonin causes compliance bigger among the psychotic to be treated.
Further consider pancreas opsonin and agonist thereof, analog or derivant, can use in conjunction with other psychosis medicines or treatment, as be generally used for antipsychotic those, as tricyclic antidepressants and monoamine oxidase inhibitor (MAOI), selectivity 5-hydroxy tryptamine reuptake inhibithors (SSRI), 5-hydroxy tryptamine and noradrenaline reuptake inhibitor (SNRI), medical herbs antidepressant (for example, St John ' s Wort or Hypericum), second filial generation antipsychotic drug (SGA), mental analysis, cognition-behavior therapy and interpersonal treatment.When in conjunction with other psychosis medicines or treatment use, the administration of pancreas opsonin or amylin agonist can take place simultaneously or according to the order of sequence with other psychosis medicines or treatment.For example, can be in the process of other identical time periods of psychosis medicine, in the eclipsed time period process of other psychosis medicines, or there are not administration pancreas opsonin or amylin agonist in the eclipsed time period with other psychosis medicine administrations.As therapeutic alliance or additional treatment, one or more adverse side effects of present available medicine can be offset or regulate to the beneficial property of pancreas opsonin or amylin agonist, for example, and weight increase, diabetes.
For example, SGA is the effective therapeutic agent that is used for the treatment of with schizophrenia and relevant mental illness symptom.Although have these advantages in the treatment mental illness, cumulative clinical data has disclosed the use of SGA and the association (Amercian Diebetes Association (2004) DiabetesCare 27:596-601 such as (ADAs)) between weight increase, diabetes and the unusual lipidemia.Weight increase may be the influence factor that the patient does not comply with medicine.Therefore, the same with any medicine, any benefit is not provided for the patient who does not take or correctly do not take.Exemplary SGA such as clozapine and olanzapine have been accredited as and have produced weight increase probably; In addition, these two kinds of SGA are also relevant with unusual lipidemia risk with the diabetes that improve.Proved for this reason that in embodiment 3 the pancreas opsonin effectively reduces the ability that clozapine is treated inductive weight increase.In addition, the treatment of diabetes and unusual lipidemia can also be treated or help to pancreas opsonin and amylin agonist.Amylin agonist, Pramlintide has obtained the FDA approval, as the auxiliary treatment of (1 type and 2 types) insulin in the treating diabetes.Therefore, when using in conjunction with other psychosis medicines, pancreas opsonin and amylin agonist not only provide the additional treatment to mental illness, and can offset at least a negative side effect of those other psychosis medicines.
As used in this, " patient " comprises any mammal, comprises the people." patient " can also comprise house pet (for example, Canis familiaris L., cat, horse), and other animals.The patient can have at least a mental disorder described herein.The patient who has benefited from method disclosed herein can be overweight or fat; Yet they also can be thin.Except mental disorder, they suffer from Metabolic disorder or disease.Exemplary Metabolic disorder comprises diabetes, metabolic syndrome, development of insulin resistance and unusual lipidemia.The patient can be any age.Therefore, these obstacles can discovery in young and adult (be defined herein as 65 years old or following those) and baby, child, teenager and old people (being defined herein as above 65 years old).In fact, the crowd of specific part tends to suffer from particular disorder especially, as teenager and young eating disorders.The old people is easy to suffer from the disease as depression so especially.
As used in this, and understood in this area, " treatment " is the method that is used to obtain useful or required result, comprises clinical effectiveness." treatment " or " alleviating " disease, obstacle or the disease meaning are not compare with treating obstacle, the degree of symptom, disadvantageous clinical presenting or both, and the degree of obstacle or morbid state, unfavorable clinical presenting alleviates and/or the time course progress is slowed down or prolonged.Purpose for method disclosed herein, useful or required clinical effectiveness comprises, but be not limited to, the alleviating or alleviate of one or more symptoms, the elimination of disease degree, stable (promptly not the worsening) of morbid state, the delay of progression of disease or slow down, the alleviation of disease or alleviate and takes a turn for the better (no matter being part or all of) regardless of being detectable or undetectable." treatment " can also look like is to prolong survival, if compare with the survival of the expection of not receiving treatment.In addition, must not treat during by the administration dose, but take place usually during a series of medicament of administration.Therefore, can be with drug treatment effective dose in single or divided doses, this be enough to palliate a disease, the content of obstacle or disease, or be enough to treat the content of disease, obstacle or disease.
As used in this, singulative " ", " a kind of " and " being somebody's turn to do " comprise that plural number refers to thing and obviously finds out unless otherwise noted or from literary composition.For example, can find out obviously from literary composition that " a kind of " amylin agonist can comprise one or more amylin agonists.
Without wishing to be bound by theory, the pancreas opsonin can be by regulating GC-response site (as brain) performance psychosis/behavior effect and giving to be subjected to usually GC (for example, CFR) expressing and active function, behavior, autonomic nervous system activity, neuroendocrine function and the metabolism of regulating).Without wishing to be bound by theory, the behavior (for example, anxiety, depression) of GC, brain CFR or chronic stress and metabolism (for example, feed, obesity) effect can be blocked or reduce to pancreas opsonin, its agonist, analog or derivant.In addition, the pancreas opsonin can have some and its anti-diabetic or anti-obesity activity not directly related antidepressant, anxiety and/or antipsychotic activity.Moreover without wishing to be bound by theory, a pancreas opsonin part works by the regulating action of regulating or otherwise impact stress pathways and/or CRF and/or GC reply the behavior that stress mediate, autonomous, neuroendocrine and metabolism.
Stress, GC and CRF look to have complicated relation in psychology and metabolic function.Stress be to the neuroendocrine in the humans and animals (for example, hypothalamic-pituitary-adrenal (HPA) axle), autonomous, behavior (for example, anxiety, depressed, substance abuse, feed) and metabolism (for example, lipidosis, the energy utilization) function has far-reaching influence (Dallman etc., (2002) Hormones, Brain, and Behavior pp 571-631, San Diego, CA USA:Academic Press.).All these effects are subjected to GC and regulate.Neuropeptide CRF mediates replying of many stress-induceds, comprises acute inhibition (Krahn etc., (1986), the Brain Research Bulletin 17:285-289 of food intake and anxiety; Dunn etc. (1990) BrainRes.Brain Res.Rev.15:71-100; Smagin etc. (1999) Am.J.Physiol.276:R1461-1468; Koob (1999) Biol.Psychiatry 46:1167-1180).GC and CRF activity are closely interdependent mutually, and constitute the physiological system (Dallman etc. (2003) Proc.Natl.Acad.Set USA 100:11696-11701) of the functional and abundant description of control behavior, autonomous, neuroendocrine and metabolic function together.
The destruction of GC and CRF relation, as by stress cause those, health is had far-reaching influence.The central action of the glucocorticoid (hydrocortisone among the mankind, the corticosterone in the rodent) by slow rising, chronic stress promotes delicious feed (for example, monosaccharide, fat).When ambrosia can utilize, because exist in a large number in modern society, chronic stress had improved ratio (Pecorara etc. (2004) the Endocrinology 145:3754-3762 of the delicious heat that is consumed; Laugero (2004) Vitamins and Hormones, 68 volumes, editor Gerald Litwack; Laugero etc. (2002) Endocrinology 143:4552-4562).This importance of replying, under the background of the GC that raises, be the lipidosis (Dallman etc. (2003) Proc.Natl.Acad.ScL USA100:11696-11701) that abdominal part or torso portion increase, this generation for cardiovascular disease is important and risk factor (Bjorntorp (1993) Obesity Research 1:206 independently; Carr etc. (2004) Diabetes53:2087-2094).In fact, endogenous GC raises, as in Gushing ' s patient, or give by the outside, as in the lupus patient, cause metabolic syndrome (trunk obesity, development of insulin resistance, hypertension, high triglyceride) (Stewart (2003) The Adrenal Cortex, Williams Textbook of Endocrinology, the 10th edition, Saunders Publishing, U.S.).In addition, the trunk obesity is characterised in that the glucocorticoid activity of raising, and be assumed to be, by the secretion of synthetic activity of adrenal cortex and GC, chronic stress (Bjorntorp (2001) Obes.Rev.2:73-86 that plays an important role in the fat and metabolic syndrome at trunk; Rosmond etc. (2000) Obes.Res.8:445-450; Bjorntorp (1997) Nutrition 13:795-803; Dallman etc. (2002) Hormones, Brain, and Behaviorpp 571-631, San Diego, CA USA:Academic Press.; Dallman etc. (2003) Proc.Natl.Acad.Sci.USA 100:11696-11701).
High-and low-cortisolemia also be the feature that psychosis fully proves, and the show abnormality excretory signal of hydrocortisone and more may have psychosis of the patient who suffers from metabolic syndrome as major depression.Think that chronic stress and relevant active raising of maincenter CRF play pivotal role (Chrousos etc., (2000) Int.J.Obes.Relat.Metab.Disord.24:S50-S55 in clinical depression, anxiety neurosis, substance abuse, eating disorders and metabolic syndrome; Koob (1999) Biol.Phychiatry 46:1167-1180).In fact, studying at present the therapeutical effect of micromolecule CRF antagonist in major depression, broad sense anxiety neurosis, eating disorders and other stress the related pathologies patients.
The pancreas opsonin is from pancreas beta cell and the common excretory hormone of insulin and has various metabolism, comprises sugared regulating action.The sugared regulating action of pancreas opsonin and its effect relevant (Young (1997) Curr.Opin.In Endocrinology and Diabetes 4:282-290) that the inhibition and the food intake of the glucagon secretion after the meal of gastric emptying, inappropriate rising are suppressed.Researching and developing the amylin agonist analog, Pramlintide, be used for the treatment of 1 type and type 2 diabetes mellitus (Baron etc. (2002) Curr.Drug Targets Immune Endocr.Matabol.Disord.2:63-82), and be used for this purposes recently by the FDA approval.Because its antidiabetic effect, the pancreas opsonin still is used for the treatment of the good candidate of metabolic syndrome.In addition, because its effect to the weight of animals, the pancreas opsonin is material standed for (Mack etc. (2003) Diabetes 52 (the augmenting 1) A389 that is used for people's obesity medicine.
Amylin agonist comprises the amylin agonist analog, and the example is described in US patent 5,686,411; US patent 6,610,824; US patent 5,998,367; US patent 6,087,334; The US provisional application no.60/617 of 10/8/04 application, 468 and PCT application No.PCT/US2005/004631 in, all are hereby incorporated by.In specific embodiment, the method that provides does not comprise the use of calcitonin.In specific embodiment, calcitonin is a salmon calcitonin see calcimar.In other embodiments, the method that provides does not comprise the use of GGRP.Still in other embodiments, the method that provides does not comprise the use of the analog of CGRP or calcitonin.Therefore, consider that the method that provides has comprised eliminating CGRP, the collateral condition of calcitonin or its analog.
" pancreas opsonin " meaning is to be called the pancreas opsonin and from the excretory people's peptide hormone of the beta cell of pancreas, and the species variant, and the example is described in U.S. patent No.5, and in 234,906, its content is hereby incorporated by.More specifically, the pancreas opsonin is to reply usually that nutrition is taken in and by pancreas beta cell and the natural together excretory 37-amino acid polypeptide hormone of insulin (referring to, for example, Koda etc. (1992) Lancet 339:1179-1180).Under this understanding, " pancreas opsonin ", " wild type pancreas opsonin " and " natural pancreas opsonin ", that is, the pancreas opsonin of unmodified can be used alternatingly.The pancreas opsonin sometimes also is called " LAPP ".
" agonist " meaning is to cause the bioactive chemical compound of pancreas opsonin, for example, by measurement known in the art, during receptors bind/competition research evaluation, has the effect that is higher than the pancreas opsonin as discussed in this, or compare with the pancreas opsonin, in five order of magnitude effects (adding deduct), for example, 4,3,2 or 1 orders of magnitude.
In one embodiment, the term agonist refers to the chemical compound that causes the biological effect similar to natural pancreas opsonin, for example chemical compound (1) has in food intake, gastric emptying, pancreatic secretion or the test that loses weight that (PCT applies for No.PCT/US2005/004631 according to the similar activity of peptide to natural ginseng, application on February 11st, 2005, and be incorporated herein by reference), and/or (2) its in reference receptor test or competitively combine with pancreas opsonin specificity in conjunction with test.In one embodiment, exciting to be higher than the affinity agent combination of 1 μ M in such test, in another embodiment, have the affinity that is higher than 1-5nM.Such agonist can comprise polypeptide or the little chemical molecular that contains pancreas opsonin active fragment.In some embodiments, agonist is a peptide, is not little chemical molecular.Yet, consider in specific embodiment, can use restricted language with salmon calcitonin see calcimar, calcitonin, CGRP and/or its receptor analogs are got rid of outside the amylin agonist scope.In specific embodiment, amylin agonist is not little chemical molecular, can use restricted language that little chemical molecular is got rid of outside the amylin agonist scope.
Agonist comprises pancreas opsonin analog and pancreas opsonin derivant." analog " meaning is such peptide: its sequence source comprises insertion from the pancreas opsonin, and displacement is extended and/or deletion, has at least some aminoacid homogeneity with the fragment of pancreas opsonin or pancreas opsonin peptide.Analog and natural pancreas opsonin have at least 50 or 55% amino acid sequence identity, or have at least 70%, 80% with natural pancreas opsonin, 90% or 95% amino acid sequence identity.In one embodiment, such analog comprises conservative or non-conservative amino acid replacement (comprising alpha-non-natural amino acid and L and D type).The amylin agonist analog is an analog described herein and as amylin agonist.
" derivant " is defined as the aminoacid sequence with natural pancreas opsonin or analog, but has one or more amino acid side groups in addition, alpha-carbon atom, the molecule of terminal amino group or terminal carboxylic acid group chemical modification.Chemical modification includes, but not limited to add chemical part, forms new key and removes chemical part.The modification of amino acid side group includes, but not limited to the acidylate of lysine epsilon-amino, the N-alkanisation of arginine, histidine or lysine, glutamic acid or aspartic acid carboxylic acid group's alkanisation and the deacylated tRNA amine of glutamine or agedoite.The modification of terminal amino group includes, but not limited to deaminizating, the N-low alkyl group, and N-two-low alkyl group, the qualification alkyl (for example, side chain, ring-type condenses, adamantyl) and the modification of N-aryl.Terminal carboxyl group is modified and is included, but not limited to amide, and the low alkyl group amide limits alkyl (side chain, ring-type condense, adamantyl) alkyl, and dialkyl amide and lower alkyl esters are modified.Low alkyl group is the C1-C4 alkyl.In addition, one or more side groups, or end group can be protected by the known blocking group of synthetic chemistry those skilled in the art.Amino acid whose alpha-carbon can be singly-or dimethylated.
People's pancreas opsonin (h pancreas opsonin or h-pancreas opsonin) has following aminoacid sequence: Lys-Cys-Asn-Thr-Ala-Thr-Cys-Ala-Thr-Gln Arg-Leu-Ala-Asn-Phe-Leu-Val-His-Ser-Ser-Asn-Asn-Phe-Gly-Ala-Ile-Leu-Ser-Ser-Thr-Asn-Val-Gly-Ser-Asn-Thr-Tyr (SEQ ID NO:1).
Rat pancreas opsonin (r pancreas opsonin) has following sequence:
KCNTATCATQRLANFLVRSSNNLGPVLPPTNVGSNTY(SEQ?ID?NO：2)。Comprise use from the pancreas opsonin of any species.
The amylin agonist that uses in the method disclosed herein comprises and is described in U.S. patent No.5,686,411,6,114,304 and 6,410,511 and the open No.WO93/10146 of PCT application in those, its content is incorporated herein by reference with its integral body at this.Such chemical compound comprises those with general formula I:
1A
1-X-Asn-Thr-
5Ala-Thr-Y-Ala-Thr-
10Gln-Arg-Leu-B
1-Asn-
15Phe-Leu-C
1-D
1-E
1-
20F
1-G
1-Asn-H
1-Gly-
25I
1-J
1-Leu-K
1-L
1-
30Thr-M
1-Val-Gly-Ser-
35Asn-Thr-Tyr(SEQ?ID?NO：3)。
A wherein
1Be Lys, Ala, Ser or hydrogen;
B
1Be Ala, Ser or Thr;
C
1Be Val, Leu or Ile;
D
1Be His or Arg;
E
1Be Ser or Thr;
F
1Be Ser, Thr, Gln or Asn;
G
1Be Asn, Gln or His;
H
1Be Phe, Leu or Tyr;
I
1Be Ala or Pro;
J
1Be He, Val, Ala or Leu;
K
1Be Ser, Pro, Leu, He or Thr;
L
1Be Ser, Pro or Thr;
M
1Be Asn, Asp or Gln;
X and Y are independently selected from that having chemically is bonded to each other and form the amino acid residue of the side chain that intramolecularly is connected.
The C-end parts can be amino, alkyl amino, and dialkyl amido, cycloalkyl amino, virtue is amino, aryl alkyl amino, alkoxyl, aryloxy group, aralkoxy or carboxyl.Comprise the group that is derived from the alkyl thiol that can form disulfide bond for X and the suitable side chain of Y; Can form the alkyl acid and the alkylamine of cyclic lactam; Can condense and reduce alkyl aldehydes or alkyl halide and the alkylamine that forms the alkylamine bridge; Maybe can be connected to form alkyl, thiazolinyl, alkynyl, the side chain of ether or thioether bond.Preferred alkyl side chain comprises having about 1 low alkyl group to about 6 carbon atoms.
The another one aspect provides the compositions of purposes and the agonist analog that method relates to SEQ ID NO:3 at this, and it is not a bridge joint, and wherein X and Y are independently selected from Ala, Ser, Cys, Val, the alkyl of Leu and Ile or Ser or Cys, aryl or aralkyl ester and ether.
Example compound includes, but not limited to des-
1Lys-h-pancreas opsonin (SEQ ID NO:4),
28Pro-h-pancreas opsonin (SEQ ID NO:5),
25,28,29Pro-h-pancreas opsonin (SEQ ID NO:6),
18Arg
25,28Pro-h-pancreas opsonin (SEQ ID NO:7) and des-
1Lys
18Arg
25,28Pro-h-pancreas opsonin (SEQ ID NO:8), all demonstrate pancreas opsonin activity in the body in the test animal of treatment, (for example, causing significant hyperlactemia after the hyperglycemia).Except having the living features of pancreas opsonin, also have been found that at this specific compound that provides and compare to have better dissolubility and stability features with people's pancreas opsonin.These examples for compounds comprise
25Pro
26Val
28,29Pro-h-pancreas opsonin (SEQ ID NO:9),
25,28,29Pro-h-pancreas opsonin and
18Arg
25,28Pro-h-pancreas opsonin.
Other chemical compounds comprise
18Arg
25,28,29Pro-h-pancreas opsonin (SEQ ID NO:10), des-
1Lys
18Arg
25,28,29Pro-h-pancreas opsonin (SEQ ID NO:11), des-
1Lys
25,28,29Pro-h-pancreas opsonin (SEQ ID NO:12),
25Pro
26Val
28,29Pro-h-pancreas opsonin (SEQ ID NO:13),
23Leu
25Pro
26Val
28,29Pro-h-pancreas opsonin (SEQ ID NO:14),
23Leu
25Pro
26Val
28Pro-h-pancreas opsonin (SEQ ID NO:15), des-
1Lys
23Leu
25Pro
26Val
28Pro-h-pancreas opsonin (SEQ ID NO:16),
18Arg
23Leu
25Pro
26Val
28Pro-h-pancreas opsonin (SEQ ID NO:17),
18Arg
23Leu
25,28,29Pro-h-pancreas opsonin (SEQ ID NO:18),
18Arg
23Leu
25,28Pro-h-pancreas opsonin (SEQ ID NO:19),
17Ile
23Leu
25,28,29Pro-h-pancreas opsonin (SEQ ID NO:20),
17Ile
25,28,29Pro-h-pancreas opsonin (SEQ IDNO:21), des-
1Lys
17Ile
23Leu
25,28,29Pro-h-pancreas opsonin (SEQ ID NO:22),
17Ile
18Arg
23Leu-h-pancreas opsonin (SEQ ID NO:23),
17Ile
18Arg
23Leu
26Val
29Pro-h-pancreas opsonin (SEQ ID NO:24),
17Ile
18Arg
23Leu
25Pro
26Val
28,29Pro-h-pancreas opsonin (SEQ ID NO:25),
13Thr
21His23Leu
26Ala
28Leu
29Pro
31Asp-h-pancreas opsonin (SEQ ID NO:26),
13Thr
21His
23Leu
26Ala
29Pro
31Asp-h-pancreas opsonin (SEQ ID NO:27), des-
1Lys
13Thr
21His
23Leu
26Ala
28Pro
31Asp-h-pancreas opsonin (SEQ ID NO:28),
13Thr
18Arg
21His
23Leu
26Ala
29Pro
31Asp-h-pancreas opsonin (SEQ ID NO:29),
13Thr
18Arg
21His
23Leu
28,29Pro
31Asp-h-pancreas opsonin (SEQ ID NO:30) and
13Thr
18Arg
21His
23Leu
25Pro
26Ala
28,29Pro
31Asp-h-pancreas opsonin (SEQ ID NO:31).
Used amylin agonist comprises pancreas opsonin family polypeptides-6 (AFP-6) analog in the method disclosed herein, as US provisional application No.60/617,468 and PCT application No.PCT/US05/036456 described in, be incorporated herein by reference with its integral body at this.Ripe AFP-6 is also referred to as melanotropin, has following aminoacid sequence TQAQLLRVGCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY (SEQ ID NO:32).AFP-6 or AFP-6 analog are can yes or no amidated at C-end.Such AFP-6 analog comprises those with general formula I I: X
1-X
2-X
3-X
4-X
5-X
6-X
7-X
8-QVQNLSHRLWQL-X
21-X
22-X
23-X
24-X
25-X
26-X
27-X
28-SAPV-X
33-PSSPHSY (SEQ ID NO:33), wherein X
1Do not exist, TQAQLLRVG (SEQ IDNO:34), any one in one or more continuous amino acids of SEQ ID NO:34 has the C1-C18 of being selected from alkyl, substituent N-aryl of the alkyl of replacement or heteroaryl moieties or N-acyl group;
X
2Be M, S, C, the L of replacement, K, D or E wherein can connect side chain by amido link, or can with X
8Form for example any aminoacid of disulfide bond or amido link of key;
X
3Be V, D, L, G, N, A or S;
X
4Be V, D, L, G, N, A, S or T;
X
5Be V, D, L, G, N, A or S;
X
6Be V, D, L, G, N, A, S or do not exist;
X
7Be T, S, Hse (homotype SER), Ahb ((S)-2-amino-3-hydroxy-3-methyl butanoic acid) or (Ahp) (2R, 3R)-2-amino-3-hydroxy-4-methyl valeric acid;
X
8Be M, S, C, the L of replacement, K, D or E, or can form for example any aminoacid of disulfide bond or amido link of key with X2;
X
21Be M, G, P, A or do not exist;
X
22Be M, G, P, A or do not exist;
X
23Be M, G, P, A or do not exist;
X
24Be M, G, P, A or do not exist;
X
25Be M, G, P, A or do not exist;
X
26Be R or do not exist, wherein X
26When not existing, X
27Do not exist;
X
27Be Q or do not exist, wherein X
27When not existing, X
26Do not exist;
X
28Be D or E;
X
33Be D or E;
And bioactive fragment.
In other embodiments, the AFP-6 analog comprises, or its active fragment comprises having the chemical compound of the aminoacid sequence of general formula (III): X
1-X
2-QNLSHRLWQL-X
13-X
14-X
15-X
16-X
17-X
18-X
19-X
20-SAPV-X
25-PSSPHSY (SEQ ID NO:35), wherein:
X
1Be Q or do not exist;
X
2Be V or do not exist;
X
13Be M, G, P, A or do not exist;
X
14Be M, G, P, A or do not exist;
X
15Be M, G, P, A or do not exist;
X
16Be M, G, P, A or do not exist;
X
17Be M, G, P, A or do not exist;
X
18Be R or do not exist, wherein X
18When not existing, X
19Do not exist;
X
19Be Q or do not exist, wherein X
19When not existing, X
18Do not exist
X
20Be D or E;
X
25Be D or E;
And bioactive fragment.
The aminoacid sequence that is used for the example AFP-6 analog of open method comprises:
RVGCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：36)
GCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：37)
CVLGTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：38)
QVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：39)
VQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：40)
VQNLSHRL-QLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：41)
TQAQLLRVGCVLGTCQVQNLSHRLWQLRQDSAPVDPSSPHSY(SEQ?ID?NO：42)
TQAQLLRVGCVLGTCQVQNLSHRLWQLDSAPVDPSSPHSY(SEQ?ID?NO：43)
VGCVLGTCQVQNLSHRLWQLRQDSAPVDPSSPHSY(SEQ?ID?NO：44)
CVLGTCQVQNLSHRLWQLRQESAPVEPSSPHSY(SEQ?ID?NO：45)
TQAQLLRVGCSNLSTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：46)
TQAQLLRVGCNTATCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：47)
RVGCGNLSTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：48)
TQAQLLRVGCDTATCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：49)
TQAQLLRVGCGNLSTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：50)
TQAQLLRVGMVLGTMQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：51)
GMVLGTMQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：52)
VGMVLGTMQVQNLSHRLWQLRQDSAPVDPSSPHSY(SEQ?ID?NO：53)
RVGCGNLSTCQVQNLSHRLWQLMGPAGRQDSAPVDPSSPHSY(SEQ?ID?NO：54)
VGCGNLSTCQVQNLSHRLWQLRQDSAPVDPSSPHSY(SEQ?ID?NO：55)
V-CNTA-TCQVQNLSHRLWQLRQDSAPVDPSSPHSY(SEQ?ID?NO：56)
GCNTATCQVQNLSHRLWQLRQDSAPVDPSSPHSY(SEQ?ID?NO：57)
TQAQLLRVGCVLGTCQVQNLSHRLWQLMGPAGRQESAPVEPSSPHSY(SEQ?ID?NO：58)
TQAQLLRVGCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVEPSSPHSY(SEQ?ID?NO：59)
GTMQVQNLSHRLWQLRQDSAPVEPSSPHSY(SEQ?ID?NO：60)
VGCVLGTCQVQNLSHRLWQLMGPAGRQDSAPVEPSSPHSY(SEQ?ID?NO：61)
VGCVLGTCQVQNLSHRLWQLRQDSAPVEPSSPHSY(SEQ?ID?NO：62)
GCNTATCQVQNLSHRLWQLRQDSAPVEPSSPHSY(SEQ?ID?NO：63)
GCSNLSTCQVQNLSHRLWQLRQDSAPVEPSSPHSY(SEQ?ID?NO：64)
GCGNLSTCQVQNLSHRLWQLRQDSAPVEPSSPHSY(SEQ?ID?NO：65)
GCVLGTCQVQNLSHRLWQLRQESAPVEPSSPHSY(SEQ?ID?NO：66)。
Used amylin agonist comprises US patent No.6 in the method disclosed herein, the analog of identifying in 087,334, and its disclosure is hereby incorporated by.Useful like this amylin agonist comprises the analog of general formula I V: X
1-Xaa
1-X
2-Xaa
2-X
3-Xaa
3-X
4-Xaa
4-X
5-Xaa
5-X
6(SEQ ID NO:67), wherein
X
1Be Lys, Arg or do not exist;
X
2Be Xaa
6Xaa
7Xaa
8Xaa
9(SEQ ID NO.68) or Z-Xaa
10If SerThr is X
2Be Z-Xaa
10SerThr, X so
1And Xaa
1Do not exist;
X
3Be AlaThr, AlaSer, SerMet, GluThr or ValThr;
X
4Be ArgLeuAla, HisLeuAla, ArgIleAla, LysIleAla, ArgMetAla, HisMetAla, LysMetAla or ArgLeuThr;
X
5Be PheLeu, PheIle, PheMet, TyrLeu, TyrIle, Ty-rMet, TrpIle or TrpMet;
X
6Be ArgSerSerGlyTyr (SEQ ID NO:69), LysSerSerGlyTyr (SEQ ID NO:70), HisSerSerGlyTyr (SEQ ID NO:71), ProSerSerGlyTyr (SEQ ID NO:72), ArgSerArgGlyTyr (SEQID NO:73), ArgThrSerGlyTyr (SEQ ID NO:74), ArgAlaSerGlyTyr (SEQ ID NO:75), AlaSerSerGlyTyr (SEQ ID NO:76), ArgSerAlaGlyTyr (SEQ ID NO:77), HisSerAlaGlyTyr (SEQID NO:78), ArgSerGlyTyr (SEQ ID NO:79), ArgSer, LysSer, HisSer, ArgThr, ProSer or Arg;
Xaa
1Be Cys or do not exist;
Xaa
2Be Cya or Ala;
Xaa
3Be Gln, Ala or Asn;
Xaa
4Be Asn, Ala or Gln;
Xaa
5Be Val, Ala, Ile, Met, Leu, amyl group Gly or butyl Gly;
Xaa
6Be Asn, Gln or Asp;
Xaa
7Be Thr, Ser, Met, Val, Leu or Ile;
Xaa
8Be Ala or Val;
Xaa
9Be Thr or Ser;
Xaa
10Be Leu, Val, Met or Ile;
Z is about 1 to the alkanoyl of about 8 carbon atoms or do not exist;
And acceptable salt on the materia medica.
It should be noted that in whole application and write refill that for example, each contains may amino acid whose amino acid position more than one with the Ma Kushi group.Consider that specially the Ma Kushi group should separately consider, therefore comprise another embodiment, and should not think separate base to the Ma Kushi group.
The amylin agonist that uses in the method disclosed herein comprises pancreas opsonin family peptides and the analog of describing among the PCT application No.PCT/US2005/004631, is incorporated herein by reference with its integral body at this.Useful like this amylin agonist can comprise the analog that contains aminoacid sequence general formula V: Xaa
1X Xaa
3Xaa
4Xaa
5Xaa
6Y Xaa
8Xaa
9Xaa
10Xaa
11Xaa
12Xaa
13Xaa
14Xaa
15Xaa
16Xaa
17Xaa
18Xaa
19Xaa
20Xaa
21Xaa
22Xaa
23Xaa
24Xaa
25Xaa
26Xaa
27Xaa
28Xaa
29Xaa
30Xaa
31Xaa
32(SEQ ID NO:80), wherein
Xaa
1Be A, C, hC (homotype Cys), D, E, F, F, I, K, hK (homotype Lys), R, hR (homotype Arg), S, Hse (homotype Ser), T, G, Q, N, M, Y, W, P, Hyp (hydroxyl Pro), H, V or do not exist;
Xaa
3Be A, D, E, N, Q, G, V, R, K, hK, hR, H, I, L, M or do not exist;
Xaa
4Be A, I, L, S, Hse, T, V, M or do not exist;
Xaa
5Be A, S, T, Hse, Y, V, I, L or M;
Xaa
6Be T, A, S, Hse, Y, V, I, L or M;
Xaa
8Be A, V, I, L, F or M;
Xaa
9Be L, T, S, Hse, V, I or M;
Xaa
10Be G, H, Q, K, R, N, hK or hR;
Xaa
11Be K, R, Q, N, hK, hR or H;
Xaa
12Be L, I, V, F, M, W or Y;
Xaa
13Be A, F, Y, N, Q, S, Hse or T;
Xaa
14Be A, D, E, G, N, K, Q, R, H, hR or hK;
Xaa
15Be A, D, E, F, L, S, Y, I, V or M;
Xaa
16Be L, F, M, V, Y or I;
Xaa
17Be H, Q, N, S, Hse, T or V;
Xaa
18Be K, hK, R, hR, H, u (Cit) or n (Orn);
Xaa
19Be F, L, S, Hse, V, I, T or do not exist;
Xaa
20Be H, R, K, hR, hK, N, Q or do not exist;
Xaa
21Be T, S, Hse, V, I, L, Q, N or do not exist;
Xaa
22Be F, L, M, V, Y or I;
Xaa
23Be P or Hyp;
Xaa
24Be P, Hyp, R, K, hR, hK or H;
Xaa
25Be T, S, Hse, V, I, L, F or Y;
Xaa
26Be N, Q, D or E;
Xaa
27Be T, V, S, F, I or L;
Xaa
28Be G or A;
Xaa
29Be S, Hse, T, V, I, L or Y;
Xaa
30Be E, G, K, N, D, R, hR, hK, H or Q;
Xaa
31Be A, T, S, Hse, V, I, L, F or Y; With
Xaa
32Be F, P, Y, Hse, S, T or Hyp;
Wherein X can form key with Y and be independently selected from that having chemically is bonded to each other and form intramolecularly and be connected residue as the side chain of disulfide bond; Amido link; Can form the alkyl acid and the alkylamine of cyclic lactam; Can condense and reduce alkyl aldehydes or alkyl halide and the alkylamine that forms alkylamine or bridge; Maybe can be connected to form alkyl, thiazolinyl.The side chain of alkynyl, ether or thioether bond.
Alkyl chain can comprise having about 1 low alkyl group to about 6 carbon atoms.In specific embodiment, intermolecular linkage can be disulfide bond, amide, imines, amine, alkyl or alkenyl key.In specific embodiments, X and Y are independently selected from Ser, Asp, GIu, Lys, Orn or Cys.In specific embodiments, X and Y are Cys and Cys.In other embodiments, X and Y are Ser and Ser.Still in other embodiments, X and Y are Asp and Lys or Lys and Asp.
Useful amylin agonist can also comprise the analog that contains aminoacid sequence general formula VI: Xaa
1Xaa
2Xaa
3Xaa
4Xaa
5Xaa
6Xaa
7Xaa
8Xaa
9Xaa
10Xaa
11Xaa
12Xaa
13Xaa
14Xaa
15Xaa
16Xaa
17Xaa
18Xaa
19Xaa
20Xaa
21Xaa
22P Xaa
24T N Xaa
27G SXaa
30Xaa
31Xaa
32(SEQ ID NO:81), wherein
Xaa
1Be A, C, D, F, I, K, S, T or do not exist;
Xaa
2Be C, D, S or do not exist;
Xaa
3Be A, D, N or do not exist;
Xaa
4Be A, L, T or do not exist;
Xaa
5Be A or S;
Xaa
6Be T, A, S or V;
Xaa
7Be C, K or A;
Xaa
8Be A, V, L or M;
Xaa
9Be L or T;
Xaa
10Be G, H, or Q;
Xaa
11Be K, R, Q or do not exist;
Xaa
12Be L, W or Y;
Xaa
13Be A, F, N, Q, S or T;
Xaa
14Be A, D, E, G, N, K, Q or R;
Xaa
15Be A, D, E, F, L, S or Y;
Xaa
16Be L or F;
Xaa
17Be H, Q, S or V;
Xaa
18Be K, R, hArg, u (Cit) or n (Orn);
Xaa
19Be F, L, S or do not exist;
Xaa
20Be H, Q or do not exist;
Xaa
21Be T, N or do not exist;
Xaa
22Be F, L, M, V or Y;
Xaa
24Be P or R;
Xaa
27Be T or V;
Xaa
30Be E, G, K or N;
Xaa
31Be A or T; With
Xaa
32Be F, P or Y.
Useful amylin agonist can also comprise the analog that contains aminoacid sequence general formula VII: Xaa
1Xaa
2Xaa
3Xaa
4Xaa
5T Xaa
7Xaa
8Xaa
9Xaa
10Xaa
11L Xaa
13Xaa
14Xaa
15L Xaa
17Xaa
18Xaa
19Xaa
20Xaa
21Xaa
22P Xaa
24T N Xaa
27G S Xaa
30Xaa
31Xaa
32, (SEQ ID NO:82), wherein
Xaa
1Be A, C, F, I, K, S or do not exist;
Xaa
2Be C, D or S;
Xaa
3Be A, D or N;
Xaa
4Be A, L or T;
Xaa
5Be A or S;
Xaa
7Be C or K;
Xaa
8Be A or V;
Xaa
9Be L or T;
Xaa
10Be G, H or Q;
Xaa
11Be K, R or hArg;
Xaa
13Be A, F, N, S or T;
Xaa
14Be A, D, E, G, N, Q or R;
Xaa
15Be A, E, F, L, S or Y;
Xaa
17Be H, S or V;
Xaa
18Be K, R, hArg, u (Cit) or n (Orn);
Xaa
19Be F, L or S;
Xaa
20Be H or Q;
Xaa
21Be T or N;
Xaa
22Be F, L, M, V or Y;
Xaa
24Be P or R;
Xaa
27Be T or V;
Xaa
30Be E, G, K or N;
Xaa
31Be A or T; With
Xaa
32Be F, P or Y.
Useful amylin agonist can also comprise the analog that contains aminoacid sequence general formula VIII: Xaa
1Xaa
2Xaa
3Xaa
4Xaa
5Xaa
6Xaa
7Xaa
8Xaa
9Xaa
10Xaa
11Xaa
12Xaa
13Xaa
14Xaa
15Xaa
16Xaa
17Xaa
18Xaa
19Xaa
20Xaa
21Xaa
22P Xaa
24T N Xaa
27G SXaa
30Xaa
31Xaa
32(SEQ ID NO:83), wherein
Xaa
1Be A, C, D, F, K, T or do not exist;
Xaa
2Be A, C, D, S or do not exist;
Xaa
3Be A, D, N or do not exist;
Xaa
4Be A, L, T or do not exist;
Xaa
5Be A or S;
Xaa
6Be A, S, T or V;
Xaa
7Be A, C or K;
Xaa
8Be A, L, M or V;
Xaa
9Be L or T;
Xaa
10Be G, H or Q;
Xaa
11Be K, Q or R;
Xaa
12Be L, W or Y;
Xaa
13Be A, N, Q, S or T;
Xaa
14Be A, D, E, G, K, N, Q or R;
Xaa
15Be A, D, E, F, L, S or Y;
Xaa
16Be F or L;
Xaa
17Be H, Q, S or V;
Xaa
18Be K or R;
Xaa
19Be F, L, S or do not exist;
Xaa
20Be H, K, Q or do not exist;
Xaa
21Be Q, T or do not exist;
Xaa
22Be F, L or Y;
Xaa
24Be P or R;
Xaa
27Be T or V;
Xaa
30Be E, K or N;
Xaa
31Be A or T; With
Xaa
32Be F, Y or do not exist.
In aspect generalized, the sequence of general formula V, VI, VII or VIII further comprises 1,2,3,4,5,6,7,8,9,10,11,12 or the modification of more displacements, insertion, deletion, extension and/or derivation.In specific embodiment, general formula V, VI, VII or VIII comprise the deletion of position 24.In specific embodiment, the sequence of general formula V, VI or VII comprises the Val that inserts between amino acid position 22 and 23.In other embodiments, the sequence of general formula V, VI or VII comprises the GIn that inserts between position 22 and 23.Still in other embodiments, the sequence of general formula V, VI or VII comprises the sequence Gln-Thr-Tyr between position 22 and 23.Still in other embodiments, the sequence of general formula V, VI or VII comprises the sequence Leu-Gln-Thr-Tyr (SEQ ID NO:84) between position 22 and 23.In another generalized aspect, the modification of general formula V, VI or VII can be held at N-.In specific embodiment, the N-end parts of general formula V, VI or VII has the octyl group glycine of interpolation.In other embodiments, the N-end parts of general formula V, VI or VII has the isocap of interpolation.Other embodiments are described among the PCT application No.PCT/US2005/004631, and are incorporated herein by reference.
With reference to people's pancreas opsonin (SEQ ID NO:1; H pancreas opsonin), rat pancreas opsonin (SEQ IDNO:2; R pancreas opsonin) and salmon calcitonin see calcimar (sCT) CSNLSTCVLGKLSQELHKLQTYPRTNTGSGTP (SEQ ID NO:85) describe shown in the position exemplary compounds that has a modification comprise,
(1-7h pancreas opsonin) (
18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:86);
(1-7h pancreas opsonin) (
11,18Arg
22Leu 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:87);
(1-7h pancreas opsonin) (
11,18Arg
24Pro 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:88);
(1-7h pancreas opsonin) (
11,18Arg 8-24sCT) (30-37h pancreas opsonin) (SEQ ID NO:89);
(1-7h pancreas opsonin) (
11,18Arg 8-21sCT) (27-37r pancreas opsonin) (SEQ ID NO:90);
(
8Va
L9Leu
10Gly 1-15h pancreas opsonin) (
18Arg 16-27sCT) (31-37h pancreas opsonin) (SEQ IDNO:91);
(
1Ala 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:92);
(
3Ala 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:93);
(
4Ala 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:94);
(
6Ala 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:95);
(
2Ala
11,18Arg 1-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:96);
(Isocap-
7Ala
11,18Arg 5-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:97);
(
4Ala
11,18Arg 1-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:98);
(
5Ala
11,18Arg 1-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:99);
(
6Ala
11,18Arg 1-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:100);
(1-7h pancreas opsonin) (
11Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:101);
(
13Ser
14Gln
15Glu 1-16h pancreas opsonin) (
17Arg
30Asn
32Tyr 17-32sCT) (SEQ IDNO:102);
(
3Ala
11,18Arg 1-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:103);
(acetyl group-
2,7Agy
11,18Arg 1-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:104);
(acetyl group-
2,7Agy 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ IDNO:105);
(Isocap-
7Ala
10Aib
11Lys (For)
17Aib
18Lys (For) 5-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:106);
(Isocap-
7Ala
10Aib
11Lys (For) 17Aib
18Lys (For) 5-24sCT) (30-37h pancreas opsonin) (SEQ ID NO:107);
(Isocap-
7Ala
10Aib
11Lys (For)
17Aib
18Lys (For) 5-22sCT) (
28,29Pro 28-37h pancreas opsonin) (SEQ ID NO:108);
(Isocap-
7Ala
10Aib
11Lys (For)
17Aib
18Lys (For) 5-21sCT) (
28,29Pro 27-37h pancreas opsonin) (SEQ ID NO:109);
(1-7h pancreas opsonin) (LLQQWQKLLQKLKQ (SEQ ID NO:110)) (
28Pro
29Arg
32Thr27-37h pancreas opsonin) (SEQ ID NO:111);
(1-7h pancreas opsonin) (LLQQLQKLLQKLKQY (SEQ IDNO:112)) (
28Pro
29Arg
32Thr 28-37h pancreas opsonin) (SEQ ID NO:113);
(
6Ser 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:114);
(
6Val 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:115);
(1-7h pancreas opsonin) (
11,18Arg 8-18sCT) (
28Pro
29Arg
32Thr 27-37h pancreas opsonin) (SEQID NO:116);
(1-7h pancreas opsonin) (
11Arg 8-17sCT) (
28Pro
29Arg
32Thr 27-37h pancreas opsonin) (SEQ IDNO:117);
(1-7h pancreas opsonin) (
11Arg 8-16sCT) (
27Tyr
28Pro
29Arg
32Thr 27-37h pancreas opsonin) (SEQ ID NO:118);
(1-7h pancreas opsonin) (
11Arg 8-15sCT) (
27Tyr
28Pro
29Arg
32Thr 27-37h pancreas opsonin) (SEQID NO:119);
(1-7h pancreas opsonin) (
11Arg 8-14sCT) (
27Tyr
28Pro
29Arg
32Thr 27-37h pancreas opsonin) (SEQ ID NO:120);
(1-7h pancreas opsonin) (
11,18Lys (For) 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:121); (
6D-Thr 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ IDNO:122);
(acetyl group-1-7h pancreas opsonin) (
11,18Lys (PEG5000) 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:123);
(acetyl group-
1Ala 1-7h pancreas opsonin) (
11Lys (PEG5000)
18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:124);
(acetyl group-
1Ala 1-7h pancreas opsonin) (
11Arg
18Lys (PEG5000) 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:125);
(1-7h pancreas opsonin) (
11,18Arg 8-21sCT) (19-27sCT) (33-37h pancreas opsonin) (SEQ IDNO:126);
(1-7h pancreas opsonin) (
11,18Arg 8-21sCT) (
18Leu 18-27sCT) (33-37h pancreas opsonin) (SEQID NO:127);
(1-7h pancreas opsonin) be (33-37h pancreas opsonin) (SEQ ID NO:128) (8-27sCT);
(
5Ser 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:129);
(1-12h pancreas opsonin) (
18Arg 13-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:130);
(1-12h pancreas opsonin) (
18Arg 13-24sCT) (30-37h pancreas opsonin) (SEQ ID NO:131);
(
5Ser
15Glu
18Arg 1-18h pancreas opsonin) (19-24sCT) (30-37h pancreas opsonin) (SEQ IDNO:132;
(
6Hse 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:133);
(
6Ahb 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ IDNO:134);
(
6Ahp 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:135);
6Thr (OPO
3H
2) 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ IDNO:136);
(
7Ala
11,18Arg 5-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:137);
(1-7h pancreas opsonin) (
11,18Orn 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:138);
(1-7h pancreas opsonin) (
11,18Cit 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:139);
(1-7h pancreas opsonin) (
11,18HomoLys 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:140);
(L-octyl group glycine-1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ IDNO:141);
(N-3,6-two oxa-s caprylyl-1-7-h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:142);
(ring (1-7)-
1Asp
7Lys
11,18Arg 1-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:143);
(ring (2-7)-
2Asp
7Lys 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQID NO:144);
(ring (2-7) h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:145);
(1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin-9Anc) (SEQ IDNO:146);
(1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin-L-octyl group glycine) (SEQ IDNO:147);
(N-dissident's acyl group-1-7-h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ IDNO:148);
(1-7h pancreas opsonin) (
11,18HomoArg 8-27sCT) (33-37h pancreas opsonin) (SEQ IDNO:149);
(
1Phe 1-7h pancreas opsonin) (
11,18Arg 8-27sCT) (33-37h pancreas opsonin) (SEQ ID NO:150);
(1-7h pancreas opsonin) (
11,18Arg 8-24sCT) (
32Thr 30-37h pancreas opsonin) (SEQ IDNO:151);
(1-7h pancreas opsonin) (
11,18Arg 8-27sCt) (33-37h pancreas opsonin lin) (SEQ ID NO:152);
(
15Glu
18Arg 1-18h pancreas opsonin) (19-24sCT) (30-37h pancreas opsonin) (SEQ IDNO:153);
(
13Ala
14Asp
15Phe 1-18h pancreas opsonin) (19-23sCT) (30-37h pancreas opsonin) (SEQ IDNO:154); With
(2-18h pancreas opsonin) be (30-36h pancreas opsonin) (SEQ ID NO:155) (19-23sCT).
Useful peptide in this compositions that provides and method, as above those, can be acid or amide form.
Also can be used for comprising in the exemplary peptides of this compositions that provides and method:
KCNTATCVLGKLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：156)
KCNTATCVLGRLSQELHRLQTLPRTNTGSNTY(SEQ?ID?NO：157)
KCNTATCVLGRLSQELHRLQTYPPTNTGSNTY(SEQ?ID?NO：158)
KCNTATCVLGRLSQELHRLQTYPRTNVGSNTY(SEQ?ID?NO：159)
KCNTATCVLGRLSQELHRLQTLPPTNVGSNTY(SEQ?ID?NO：160)
KCNTATCVLGRLANFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：161)
ACNTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：162)
KCNAATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：163)
KCNTAACVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：164)
CANLSTCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：165)
Dissident acyl group-STAVLGRLSQELHRLQTYPRTNTGSNTY (SEQ IDNO:166)
CSNASTCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：167)
CSNLATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：168)
CSNLSACVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：169)
KCNTATCVLGRLSQELHKLQTYPRTNTGSNTY(SEQ?ID?NO：170)
KCNTATCVLGRLSQELHRLQTYPRTNTGSGTP(SEQ?ID?NO：171)
CSALSTCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：172)
Ac-(Agy)SNLST(Agy)VLGRLSQELHRLQTYPRTNTGSNTY(SEQ?IDNO：173)
Ac-K(Agy)NTAT(Agy)VLGRLSQELHRLQTYPRTNTGSNTY(SEQ?IDNO：174)
Dissident acyl group-STAVL (Aib) RLSQELRLQTYPRTNTGSGTP (SEQ IDNO:175)
Dissident acyl group-STAVLG[K (For)] LSQELH[K (For)] LQTYPRTNTGSGTP (SEQ ID NO:176)
Dissident acyl group-STAVL (Aib) [K (For)] LSQEL (Aib) [K (For)] LQTYPRTNTGSNTY (SEQID NO:177)
Dissident acyl group-STAVL (Aib) [K (For)] LSQEL (Aib) [K (For)] LQTYPRTNVGSNTY (SEQID NO:178)
KCNTATCLLQQLQKLLQKLKQYPRTNTGSNTY(SEQ?ID?NO：179)
KCNTASCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：180)
KCNTAVCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：181)
KCNTATCVLGRLSQELHRYPRTNTGSNTY(SEQ?ID?NO：182)
KCNTATCVLG[K(For)]LSQELH[K(For)L]QTYPRTNTGSNTY(SEQID?NO：183)
KCNTA(d-Thr)CVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?IDNO：184)
KCNTA(dAh)CVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?IDNO：185)
Ac-ACNTATCVLGRLSQELHK(PEG5000)LQTYPRTNTGSNTY(SEQID?NO：186)
KCNTATCVLGRLSQELHRLQTLQTYPRTNTGSNTY(SEQ?IDNO：187)
KCNTATCVLGRLSQELHRLQTLLQTYPRTNTGSNTY(SEQ?IDNO：188)
KCNTATCVLGKLSQELHKLQTYPRTNTGSNTY(SEQ?ID?NO：189)
KCNTSTCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：190)
KCNTATCATQRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：191)
KCNTATCATQRLSQELHRLQTYPRTNVGSNTY(SEQ?ID?NO：192)
KCNTSTCATQRLANELVRLQTYPRTNVGSNTY(SEQ?ID?NO：193)
KCNTA(Hse)CVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?IDNO：194)
KCNTA(Ahb)CVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?IDNO：195)
KCNTA(Ahp)CVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?IDNO：196)
KCNTAT(OPO
3H
2)CVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?IDNO：197)
KCNTATCVLG(Orn)LSQELH(Orn)LQTYPRTNTGSNTY(SEQ?IDNO：198)
KCNTATCVLG(Cit)LSQELH(Cit)LQTYPRTNTGSNTY(SEQ?IDNO：199)
KCNTATCVLG(hK)LSQELH(hK)LQTYPRTNTGSNTY(SEQ?IDNO：200)
L-octyl group glycine KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQID NO:201)
N-3,6-two oxa-caprylyl-CNTATCVLGRLSQELHRLQTVPRTNTGSNTY (SEQ ID NO:202)
KCNTATCMLGRYTQDFHRLQTYPRTNTGSNTY(SEQ?ID?NO：203)
DSNLSTKVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：204)
KDNTATKVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：205)
CNTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：206)
KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY(9Anc)(SEQ?IDNO：207)
KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (L-octyl group glycine) (SEQ ID NO:208)
N-dissident acyl group-KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQID NO:209)
KCNTATCVLG(hR)LSQELH(hR)LQTYPRTNTGSNTY(SEQ?IDNO：210)
FCNTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：211)
KCNTATCVLGRLSQELH(Cit)LQTYPRTNTGSNTY(SEQ?ID?NO：212)
KCNTATCVLGRLSQELH(Orn)LQTYPRTNTGSNTY(SEQ?IDNO：213)
ICNTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：214)
1-octyl group glycine-CNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQID NO:215)
Dissident acyl group-CNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ IDNO:216)
KCNTATCVLG(Cit)LSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：217)
KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY(4ABU)(SEQ?IDNO：218)
Dissident acyl group-KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (4ABU) (SEQ ID NO:219)
KCNTSTCATQRLANELVRLQTYPRTNVGSEAF(SEQ?ID?NO：220)
KCNTATCVLGRLSQELHRLQTYPTNVGSEAF(SEQ?ID?NO：221)
KCNTATCVLGRLSRSLHRLQTYPRTNTGSNTY(SEQ?ID?NO：222)
KCNTATCVTHRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：223)
KCNTATCVLGRLADFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：224)
CNTATCVLGRLSQELHRLQTYPRTNTGSNT(SEQ?ID?NO：225)
KCNTATCVLGRLSQELHRLQNFVPRTNTGSNTY(SEQ?ID?NO：226)
KCNTATCVLGRLSQELHRLQTYPRTNTGSETF(SEQ?ID?NO：227)
ACDTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：228)
KCNTATCVLGRLSQELHRLQTYPRTNTGSKAF(SEQ?ID?NO：229)
KCDTATCVTHRLAGLLSRSQTYPRTNTGSNTY(SEQ?ID?NO：230)
KCNTATCVLGRLADALHRLQTYPRTNTGSNTY(SEQ?ID?NO：231)
KCNTATCVLGRLAAFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：232)
SCNTATCVLGRLADFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：233)
KCNTATCVLGRLSQELHRLQTMPRTNTGSNTY(SEQ?ID?NO：234)
KCNTATCVLGRLSQELHRLQTVPRTNTGSNTY(SEQ?ID?NO：235)
KCNTATCVLGRLNEYLHRLQTYPRTNTGSNTY(SEQ?ID?NO：236)
SCNTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：237)
KCNTATCVLGRLTEFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：238)
KCNTATCVLGRLAEFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：239)
KCNTATCVLGRLTDYLHRLQTYPRTNTGSNTY(SEQ?ID?NO：240)
KCNTATCVLGRLAQFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：241)
KCNTATCVLGRLADFLHRFQTFPRTNTGSNTY(SEQ?ID?NO：242)
KCNTATCVLGRLADFLHRFHTFPRTNTGSNTY(SEQ?ID?NO：243)
KCNTATCVLGRLADFLHRFQTFPRTNTGSGTP(SEQ?ID?NO：244)
CNTATCVLGRLADFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：245)
KCDTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：246)
KCNTATCVLGRLFDFLHRLQTYPRTNTGSNTY(SEQ?ID?NO：247)
KCNTATCVLGRLAAALHRLQTYPRTNTGSNTY(SEQ?ID?NO：248)
TCDTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：249)
CSNLSTCATQRLANELVRLQTYPRTNVGSNTY(SEQ?ID?NO：250)
KCNTATCATQRLANELVRLQTYPRTNVGSNTY(SEQ?ID?NO：251)
CSNLSTCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：252)
KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY(SEQ?ID?NO：253)。
In some embodiments, comprise that the chemical compound of aminoacid sequence KCNTATCVLGRLSQELHRLQTYPRTNTGSNTY (SEQ ID NO:253) is particularly useful in disclosed method.
The derivant of agonist and analog is also included within the method that provides, and wherein the spatial chemistry of single amino acids can be to be turned into (D)/R in one or more specificitys site from (L)/S.Glycosylation modified agonist and analog by Asn, Ser and/or Thr residue also are provided in the method that provides.Useful chemical compound can also be the bioactive fragment of peptide described herein (natural, agonist, analog and derivant) in the method that provides.
The agonist and the analog that contain the pancreas opsonin of less peptide feature are included in the method that provides.Such peptide mimics can comprise, the replacement of one or more for example ,-CO--NH--amido link: (CO--O-), (CH2-NH-), (--CH=CH-), (～C (=CH～CN)～NH～), thioamides (--are CS-NH-), (S--CH2～or--CH2-S-), methylene (CH2-C2～) and retro-amide (--are NH--CO-) for thio-methylene for β-enamino nitrile for trans-alkene for the imino group methylene for the depsipeptide peptide.
The chemical compound that uses in the method that provides and various inorganic and organic bronsted lowry acids and bases bronsted lowry form salt.Such salt comprises the salt for preparing with mineral acid with organic, for example, and HCl, HBr, H
2SO
4, H
3PO
4, trifluoracetic acid, acetic acid, formic acid, methanesulfonic acid, toluenesulfonic acid, malic acid, fumaric acid and camphorsulfonic acid.Salt with alkali preparation comprises, for example, and ammonium salt, alkali metal salt (as sodium and potassium salt) and alkali salt (as calcium and magnesium salt).In specific embodiment, compound formation acetate, hydrochlorate and trifluoroacetate.
Useful amylin agonist can also comprise the fragment of aforesaid pancreas opsonin and analog thereof and be described among the EP289287 those in this compositions that provides and method, and its content is hereby incorporated by.The amylin agonist analog can also be to have with SEQ IDNO:1 or at the chemical compound with active any pancreas opsonin analog at least 60,65,70,75,80,85,90,95 of pancreas opsonin or 99% amino acid sequence identity of this special description.Amylin agonist also comprises little chemical molecular and non-peptide molecule, for example, and based on those of micromolecule chemistry.In some embodiments, amylin agonist is not little chemical molecular.
" pancreas opsonin activity " comprises the activity known in the art of at least a the following stated as used in this.Pancreas opsonin activity comprises that also the pancreas opsonin regulates stress response in vivo, influences GC and/or influence the active ability of CFR.Ideal amylin agonist or pancreas opsonin analog have in embodiment 2 and 3 the total at least a characteristic of psychosis, antidepressant and anxiety medicament as used herein.The amylin agonist analog also comprise SEQ ID NO:1 or in insertion, the deletion of at least one or a plurality of amino acid positions of any pancreas opsonin analog of this special description, extend, block and/or replace.Aminoacid insertion, deletion or metathetical quantity can be 5,10,15,20 or 25 aminoacid insertion, deletion or displacements at least.Aminoacid insertion, deletion or metathetical quantity can be no more than 5,10,15,20,25 or 30 aminoacid insertion, deletion or displacements.Can insert, extend or displacement with other natural amino acids, synthesizing amino acid, peptide analogues or other chemical compounds.Consider in specific embodiments, amylin agonist, useful in specific embodiments, do not comprise calcitonin and/or CGRP.For example, in specific embodiments, in treatment dysthymic disorder, anxiety neurosis or material associated disorders, calcitonin and/or CGRP are got rid of outside the amylin agonist scope.Yet, as sleep or eating disorders, calcitonin and/or CGRP can be included in the scope of amylin agonist for other diseases.Similarly, in specific embodiments, amylin agonist, useful in the method that provides, do not comprise calcitonin and/or CGRP analog.
Usually, think that amylin agonist or amylin agonist analog refer to and direct or indirect interaction of one or more receptors or bonded chemical compound, the effect of simulation pancreas opsonin.Also they are called pancreas opsonin analogies.
Can be by carrying out various filler tests or by inducing the mammal low blood calcium or the ability of hypercalcemia after the meal of reducing confirms and quantitatively as the activity of amylin agonist and/or analog, filler test comprises according to the test of volt nucleus receptors bind, the musculus soleus test, the gastric emptying test.The active method of pancreas opsonin of test compounds is known in the art.The example screening technique of test amylin agonist and test description, are hereby incorporated by in 264,372 nuclears 5,686,411 in U.S. patent No.5.
The competition test of compound specificity binding film in conjunction with the ability of amylin receptor measured in the receptors bind test.The preferred source of the film preparation that uses in the test is a basal forebrain, and it comprises from the film according to volt nucleus and peripheral part.The test chemical compound with
125The competition of I Bolton Hunter rat pancreas opsonin is subjected to body preparation in conjunction with these.Competition curve, wherein bonded content (B) is made curve as the log function of ligand concentration, by computer analysis, use by nonlinear regression 4-parameter logical equation (INPLOT program, GraphPAD Software, San Diego, CA) or the ALLFIT program (ALLFIT of Delean etc., 2.7 version (NIH, Bethesda, Md.20892)) analysis.Munson etc. (1980) Anal.Biochem.107:220-239.
Described method (Leighton etc. (1988) Nature 335:632-635 before can using; Cooper etc. (1988) Proc.Natl.Acad.ScL.USA 85:7763-7766) carries out the bioactive test of amylin agonist/analog in the musculus soleus, wherein can measure the amylin agonist activity by the synthetic inhibition of glycogen of measuring insulin stimulating.In brief, illustrative methods comprises from the male Wistar rat of 12-h fasting and makes the musculus soleus bar.The tendon that before connecting the rustless steel chip, connects muscle.Strip of muscle is being contained 3.5ml Krebs-Ringer bicarbonate buffer agent, 7mM N-2-ethoxy-piperazine-N '-2-ethane-sulfonic acid, preincubate in the conical flask of pH7.4 and 5.5mM pyruvate.With flask sealing and with 19: 1 ratio (v/v) O
2And CO
2Continuous charge.Muscle in this medium in 37 ℃ of vibration water-baths preincubate after 30 minutes, strip of muscle is transferred in the similar bottle that contains same media (except pyruvate), contain [the U-of interpolation
14C] glucose (0.5 μ Ci/ml) and insulin (100 μ U/ml).Inflation once more in hatch with flask sealing and at 1-h initial 15 minutes.When the stage of hatching finishes, muscle blotted and quick freezing in liquid nitrogen.Can hatch in the medium Lactated concentration and measure [the U-that introduces in the glycogen by spectrophotometric determination
14C] glucose.
The method of measuring gastric emptying rate is described in, for example, and among Young etc. (1995) Diabetologia38:642-648.In the phenol red method, conscious rat accepts to contain the acoloric gel of methylcellulose and phenol red indicator by tube feed.Behind the tube feed 20 minutes, use halothane with Animal Anesthesia, expose stomach and clamp at pylorus and lower oesophageal sphincter place, take out and open and put into alkaline solution.The stomach inclusions is derived from the phenol red intensity in the alkaline solution, measures by the absorption value at 560nm wavelength place.In tritiate glucose method, with the glucose of tritiate in the conscious rat tube feed water.By tail rat is leniently limited, use lignocaine its most advanced and sophisticated anesthesia.Collect the tritium from the blood plasma of afterbody blood separation and in beta-counter, detect at each time point.Usually gave test compounds in one minute in the tube feed precontract.
The amylin agonist chemical compound presents in the receptors bind test and is less than about about activity of 1 to 5nM greatly, is lower than about 1nM in some embodiments, is lower than about 50pM in some embodiments.In the musculus soleus test, the amylin agonist compound exhibits goes out to be less than about about 1 to 10 micromolar EC greatly
50Value.In the gastric emptying test, the amylin agonist compound exhibits goes out the ED that is less than about 100 μ g/ rats greatly
50Value.
In an illustrative methods of preparation chemical compound, can use the preparation of standard solid phase peptide synthetic technology at this chemical compound that provides, for example use automatization or semi-automatic peptide synthesizer.Usually; use such technology; the aminoacid of α-N-carbamyl protection and be connected resin on grow in the aminoacid of peptide chain in the room temperature combination; in atent solvent, as dimethyl formamide, N-Methyl pyrrolidone or carrene; in the presence of coupling agent; as dicyclohexylcarbodiimide and I-hydroxybenzotriazole, in the presence of base, as diisopropylethylamine.Use reagent such as trifluoracetic acid or piperidines to remove α-N-carbamyl blocking group, and repeat coupling reaction with the next required N-protected aminoacid to peptide chain to be added from resulting peptide-resin.Suitable N-protected group is well known in the art, at this preferred tertiary butoxy carbonyl (tBoc) and fluorenylmethyloxycarbonyl (Fmoc).Additive method synthetic or expression pancreas opsonin and amylin agonist and purification is well known by persons skilled in the art.
Preparation/administration/dosage
Pancreas opsonin, amylin agonist, pancreas opsonin analog and pancreas opsonin derivant (in this part, being called " chemical compound ") at this can be individually dosed or bound drug learn and go up acceptable carrier or excipient, with the single or multiple dosed administration.Can prepare these medical compoundss according to routine techniques with acceptable carrier on the materia medica or diluent and any other known adjuvant and excipient, as be disclosed in those of Remington ' s PharmaceuticalScience (a thunderous pharmaceutical science) of E.W.Martin.Can also augment 42:2S referring to (1988) Journalof Parenteral Science and Technology Technical Report No.10 such as Wang.
Usually, chemical compound can be mixed with stable and the safe drugs compositions is used to deliver medicine to the patient.The pharmaceutical preparation that is intended for use in the said method can comprise about 0.01 to 6.0% (w/v), or 0.05 to 1.0% chemical compound; The acetate of about 0.02 to 0.5% (w/v), phosphate, citrate or glutamate, Glu buffer agent, the pH that makes final composition are about 3.0 to about 7.0; The carbonate of about 1.0 to 10% (w/v) or polyhydric alcohol tonicifier and randomly, about 0.005 to 1.0% (w/v) antiseptic is selected from m-cresol, benzyl alcohol, methyl-, ethyl-, propyl group-and butyl-p-Hydroxybenzoate and phenol.If the peptide of preparation will be included in the multipurpose product, generally include such antiseptic.
In specific embodiment, pharmaceutical preparation can contain the chemical compound of various concentration, for example, in this embodiment, about 0.01% to about 98% (v/v), or about 1 to about 98% (w/v), or 80% to 90% (w/v), or about 0.01% to about 50% (w/v), or about 10% to about 25% (w/v).Can use the water that is used to inject of capacity to obtain required solution concentration.
If desired, can also there be other tonicifying agent, as sodium chloride, and other known excipient.In some cases, such excipient is used to keep the whole tension force of preparation.Excipient can be included in the preparation described herein with various concentration.For example, can be with about 0.02% to about 20% (w/w), about 0.02% and 0.5% (w/w), about 0.02 to about 10% (w/w), or about 1% concentration range to about 20% (w/w) comprises excipient.In addition, similar in preparation of the present invention itself, can comprise excipient with solid (comprising Powdered), liquid, semisolid or gel form.
As described herein, various liquid-carriers are applicable in the peptide formulations of the present invention, for example, and water or moisture/ORGANIC SOLVENT MIXTURES or suspending agent.Pharmaceutical preparation can constitute various forms, for example, and solid, semisolid or liquid.Term " solid " as used in this, the meaning is to comprise all the normal uses of this term, includes but not limited to powder and lyophilized formulations.Preparation described herein can be freeze dried.
Term buffer agent, buffer agent solution and buffering solution, when using about hydrogen ion concentration or pH, the ability of opposing pH change when referring to system particularly aqueous solution is when adding acid or alkali or with solvent dilution.The feature of the buffer solution that the pH that experience is little when adding acid or alkali changes is weak acid and salt of weak acid, or the existence of weak base and weak base salt.The example of said system is acetic acid and sodium acetate.The change of pH is slight, as long as hydrogen ion that adds or hydroxyl ion content do not surpass its ability of buffer system neutralization.
During liquid form, maintain about 3.0 stability that improve peptide formulations to about 7.0 the scope by pH with preparation.In one embodiment, the pH of preparation is maintained in about scope of 3.5 to 5.0, or about 3.5 to 6.5, or about 3.7 to 4.3, or about 3.8 to 4.2.Specific pH can be about 4.Although do not wish to be bound by this theory, be appreciated that in some embodiments wherein the pH of pharmaceutical preparation surpasses 5.5, can quicken the chemical degradation of peptide, make the shelf-life be lower than about 2 years.
In some embodiments, used buffer agent is that (the preparation final concentration is about 1-5mM to acetate buffer usually in the inventive method practice, for example, 1.5mM is to about 60mM), (common preparation final concentration is about 1-5mM to phosphate buffer, for example, 1.5mM, to about 30mM) or the glutamate, Glu buffer agent (common preparation final concentration is about 1-5mM, for example, 1.5mM, to about 60mM).In one embodiment, buffer agent is that the preparation final concentration is the acetate of about 5mM to about 30mM.
Stabilizing agent can be included in the preparation of the present invention, but importantly, optional.Yet if comprise, useful stabilizing agent is carbohydrate or polyhydric alcohol in the preparation practice of the present invention.Useful suitable stabilizers is about 1.0 to 10% (w/v) carbohydrate or polyhydric alcohol in the inventive method practice.Polyhydric alcohol has identical feature with carbohydrate in their main chain, that is ,-CHOH-CHOH-, this is responsible for stable protein.Polyhydric alcohol comprises such chemical compound, as Sorbitol, mannitol, glycerol and Polyethylene Glycol (PEG).These chemical compounds are straight chain molecules.Carbohydrate as mannose, ribose, sucrose, fructose, maltose, inositol and lactose, on the other hand, is a ring molecule, can contain ketone or aldehyde radical.Verified this two compounds is effective in the stable protein antagonism by temperature that raises and degeneration freeze-thaw or that the lyophilizing processing causes.The patient suffers from the embodiment of diabetes therein, suitable carbohydrate comprises: galactose, arabinose, lactose or diabetics is not had any other carbohydrate of side effect, that is, not metabolism of carbohydrate forms unacceptable big concentration glucose in the blood.The suitable carbon hydrate that is applicable to diabetes is well known in the art.Sucrose and fructose are applicable in ND's the chemical compound.
In specific embodiment, if comprise stabilizing agent, come stable compound with polyhydric alcohol, as Sorbitol, mannitol, inositol, glycerol, xylitol and polypropylene glycol/glycol copolymer, and the various PEG of molecular weight 200,400,1450,3350,4000,6000 and 8000.Mannitol is the example of special polyol.The another kind of useful feature of lyophilized formulations described herein is to be used for keeping the tension force that stable same preparation becomes to assign to keep lyophilized formulations.Mannitol is to be used for this purpose special polyol.
American Pharmacopeia (USP) advocates that the antimicrobial that must will kill antibacterial or antifungal concentration adds in the preparation that contains in the multi-dose container.They must exist with suitable concentration in use to prevent with hypodermic needle and syringe or the breeding of the microorganism in the inappropriate introducing preparation when using other invasion load modes such as pen-type injectors to take out the part inclusions.Should estimate antimicrobial and guarantee compatiblely, and should estimate their abilities in whole preparations and guarantee that in a kind of preparation effectively predetermined substance is not invalid in another kind with the every other composition of preparation.Specific antimicrobial in a kind of preparation effectively and invalid in another kind of preparation be uncommon discovery.
In medicine meaning commonly used, antiseptic is to prevent or suppress growth of microorganism and add the material of avoiding subsequently the preparation by microorganism to go bad in pharmaceutical preparation for this purpose.Although the content of antiseptic is not very big, can influence the stability in the large of peptide in any case.
Can be 0.005 to 1.0% (w/v) although be used for the antiseptic of pharmaceutical composition, the usual range of every kind of antiseptic, separately or in conjunction with other, be the compositions of p-Hydroxybenzoate of: benzyl alcohol (0.1-1.0%), metacresol (0.1-6.0%) or phenol (0.1-0.8%) or methyl-(0.05-0.25%) and ethyl-or propyl group-or butyl-(0.005%-0.03%).P-Hydroxybenzoate is the lower alkyl esters of P-hydroxybenzoic acid.The detailed description of every kind of antiseptic is listed in " Remington ' s Pharmaceutical Sciences " (Lei Mingdun pharmaceutical science) and Pharmaceutical Dosage Forms:Parenteral Medication (pharmaceutical dosage form: non-intestinal medicine), Vol.1, the 2nd edition, editors such as Avis, Mercel Dekker, New York, N.Y. (1992).
Pramlintide, 25,28,29Pro-h-pancreas opsonin does not have the trend on glass to the glass container that absorbs during with liquid form, therefore, do not need further stabilised pharmaceutical preparation of surfactant.Yet the chemical compound that has this trend during about liquid form should use surfactant in their preparation.Then with these preparation lyophilizing.Surfactant causes proteinic degeneration usually, destroys and separates by salt bridge by hydrophobicity.Because intensive interaction between the reactive site on surfactant part and the protein, the surfactant of low concentration is brought into play effective degeneration activity relatively.Yet this interactional wise use can resist interface or surface modification by stable protein.Further the surfactant of stabilized peptide can be chosen existence wantonly, scope with the total preparation of about 0.001 to 0.3% (w/v), and comprise that polysorbate 80 (promptly, polyoxyethylene (20) sorbitan monoleate), CHAPS (promptly, 3-[(3-gallbladder amido propyl) dimethylamino] 1-propane sulfonic acid inner salt), BRIJ (for example, Bril35, it is (polyoxyethylene (23) lauroyl ester), poloxamer or another kind of non-ionic surface active agent.
The tension force that adding sodium chloride or other salt are regulated pharmaceutical preparation also is ideal, depends on selected tension regulator.Yet, this be choose wantonly and depend on selected particular formulations.Parenteral formulation is normally isoosmotic or isoosmotic basically.
The suitable carrier that is used for non-enteral product is a water.The water for preparing the appropriate mass that is used for parenterai administration by diafiltration or anti-phase infiltration.Water for injection is the preferred aqueous carrier that is used for the injectable drug preparation.
Possible is that other compositions may reside in the pharmaceutical preparation.Other compositions like this can comprise; for example; wetting agent, emulsifying agent, oil, antioxidant, filler, tension regulator, chelating agen, metal ion, oily carrier, protein are (for example; human serum albumin, gelatin or protein) and amphion is (for example; aminoacid is as betanin, taurine, arginine, glycine, lysine and histidine).In addition, polymer solution, or provide the chance of peptide controlled release with mixture of polymers.Certainly, the stability in the large of adverse effect in this pharmaceutical preparation that provides should be provided other such compositions.
Container also is the whole part of ejection preparation and can thinks a kind of composition, is inert fully because there is not container, or do not influence the liquid that it contains in some aspects, if particularly liquid is aqueous.Therefore, being used for the container selection of specific injection must be based on container and solution composition and wait the consideration accepting to handle.If desired, also can use borosilicate glass, for example, I type glass #33 (Wheaton type 1-33) or its equivalent (Wheaton GlassCo.) minimize the absorption of peptide to the bottle glass surface.Other manufacturers that similar borosilicate glass bottle and syringe are suitable for making comprise Kimbel Class Co., West Co., Bunder GlasGMBH and Forma Vitrum.Can be by the biological and chemical feature of in Wheaton type 1-33 borosilicate serum bottle, in the presence of 5% mannitol and 0.02% Tween 80, preparing and lyophilizing comes stable compound to the chemical compound of 0.1mg/ml and 10.0mg/ml final concentration.
Shut in order to allow to introduce pin the multiple dose vials and provide as quickly as possible when pin takes out again from hypodermic syringe, the opening of each bottle with the rubber closure sealing, keeps by aluminium strip at correct position usually.The stopper that is used for vial, as, the stopper of West 4416/50,4416/50 (surface, Teflon) and 4406/40, Abbott 5139 or any equivalence can be as the sealing of injectable drug.Other compositions of these stoppers and peptide and preparation are compatible.When using the patient to use the pattern test, these stoppers are by the stopper integrity test, and for example, stopper is stood at least about 100 injections.Perhaps, peptide can be freeze dried in bottle, syringe or syringe, is used for reconstruction subsequently.One or two Room syringes the liquid preparation that provides at this can be provided, or in one or two chamber syringes.
Every kind of composition of said medicine preparation is known in the art and is described in PharmaceuticalDosage Forms:Parenteral Medication (pharmaceutical dosage form: parenterai administration), Vol.1, the 2nd edition, editors such as Avis, Mercel Dekker, New York, N.Y.1992 is incorporated herein by reference with its integral body at this.
The preparation process of aforesaid liquid preparation generally includes mixing, aseptic filtration and filling step.Mixed method comprises composition with specific order dissolving (for example, antiseptic then is stabilizing agent/tension regulator, buffer agent and peptide) or dissolving simultaneously.
Interchangeable preparation, for example parenteral, do not need sterilization.Yet if sterilization is ideal or essential, any suitable sterile method can be used to produce the peptide pharmaceutical preparation that provides at this.Common sterilizing methods comprises filtration, steam (damp and hot), xeothermic, gas (for example, ethylene oxy, formaldehyde, chlorine dioxide, expoxy propane etc.), is exposed to radiation source and sterile working.Filtration is the example sterilizing methods that is used for liquid preparation described herein.Aseptic filtration comprises the filtration by 0.45 μ m that can contact and 0.22 μ m (1 or 2).After the filtration, in the bottle or container that it is suitable that solution is packed into.
In one embodiment, determine that liquid pharmaceutical formulation is used for parenterai administration.Suitable route of administration comprises in intramuscular, intravenous, subcutaneous, Intradermal, intra-arterial, the sheath etc.The subcutaneous administration approach is a kind of special approach.It is also suitable especially that mucosa transmits.These mucosal route include, but not limited to mouth, nose, Sublingual, pulmonary and cheek approach, and it can comprise the administration of liquid, semisolid or solid form peptide.Administration by these approach needs more peptide to obtain required biological effect basically, owing to transmit the bioavailability of comparing and reducing with non-intestinal.In addition, by forming polymeric microcapsule, substrate, solution, implant and device and can obtaining non-intestinal controlled release transmission with their non-intestinals or by the administration of surgical operation mode.The case description of controlled release formulation is in U.S. patent No.6, in 368,630,6,379,704 and 5,766,627, is introduced into as a reference at this.Because some peptides are captured in polymeric matrix or the device, these dosage forms have lower bioavailability.Referring to, for example, U.S. patent No.6,379,704,6,379,703 and 6,296,842.
Can provide chemical compound with dosage unit form, contain chemical compound with the adverse side effect effective dose of one or more dosage treatment or help treatment psychosis and/or psychiatric treatment/medicine.Be familiar with as those skilled in the art, the effective dose of therapeutic agent will change according to many factors, comprise patient's age and body weight, patient's body situation, disease and other factors to be treated.
Yet common dosage contains the upper limit of the lower limit of about 1 μ g every day, 5 μ g, 10 μ g, 50 μ g to 100 μ g medical compoundss to about 100 μ g, 500 μ g, 1mg, 5mg, 10mg, 50mg or 100mg medical compounds.Also consider other dosage ranges, as every dose of 0.1 μ g to 1mg chemical compound.Therefore, example dosage can be every dose of 30,60,120,240 or 360 μ g chemical compound.The dosage of every day can transmit with the unit dose of separating or any part in 24 hour stage or 24 hour stage provides continuously.The dose quantity of every day is 1 to about 4 dosage every days, although can be more.Transmission can be the form of continous pouring continuously.Example dosage and infusion rate comprise 0.005pmol/kg about 0.01/pmol/kg/min about 10pmol/kg/min extremely to each dosage that separates of about 20nmol/kg or in inculcating continuously.Can transmit these dosage and inculcate by intravenous administration (i.v.) or subcutaneous administration (s.c.).Example i.v. administered agents total dosage of composition/transmission can about 2 μ g to about 8mg every day, and s.c administered agents total dosage of composition/transmission can about 6 μ g extremely about 16 or 24mg every day.
Following examples explanation is provided, but unrestricted the present invention.
Embodiment
With male, Sprague-Dawley rat acceptance sugar stops example and observes stress be to the effect of sugar absorption.In brief, rat is implanted the ALZET osmotic pumps that contains carrier or rat pancreas opsonin (300 μ g/kg/d).All rats provide ad libitum access standard food, water and 30% sucrose beverage.Subsequently, remove the sucrose beverage and half rat is accepted 3h appropriateness Restraint Stress every day, for three days on end.After 3 days, sucrose is provided and in 4 days, measures mean consumption every day.Also stop and stress 3 days in and measure food intake in when sucrose is introduced once more subsequently 4 days.In 4 days processes that sucrose is introduced once more, do not use constraint.The results are shown among Fig. 1 of this test wherein analyzed by ANOVA and Fisher LSD post-hoc, and * is P＜0.05.
In this model, chronic stress stimulates the ratio as the total amount of heat of Sugar intake.As shown in Figure 1A, by fetter the inductive consumption ratio (as the % of baseline) that stress significantly improve average sucrose and food (saline, R), surpass the contrast consumption that do not have stress-induced (saline, C).Figure 1A has shown that also the administration of pancreas opsonin has prevented the raising of average sucrose to the food consumption ratio, this raising expection as constraint inductive stress the result.Relatively the rat of the stress-induced of pancreas opsonin-administration (the pancreas opsonin, R) and pancreas opsonin-administration non-stress control rats (the pancreas opsonin, C) sucrose between is to the ratio of food.Also compared the stress-induced of pancreas opsonin-administration rat (the pancreas opsonin, R) and the rat of the stress-induced of control vector (saline) administration (saline, R) sucrose between is to the ratio of food.As directed, the administration of pancreas opsonin has reduced replying of this stress-induced.Therefore, as if the administration of pancreas opsonin reduces or protects anti-stress and influence thereof.
Figure 1B has described from the different viewpoints of the food consumption identical result from the Restraint Stress test.Although think and stress improve delicious feed (for example, monosaccharide), stress reduce the consumption (for example, standard food) of not too delicious food, this be a kind of to stress the typical case reply.Consistent with this viewpoint, what do not have the administration of pancreas opsonin stress significantly reduce the food consumption that stands the Restraint Stress animal.For example, the food consumption between the control animal of the constraint animal of comparison saline treatment and saline treatment among Figure 1B.The administration of pancreas opsonin also protect antagonism this to stress behavior reply, as by shown in the food intake data among Figure 1B.
As described above, stress be by the mediation of maincenter CFR path to the acute effect (Smagin etc. (1999) Am.J.Physiol.276:R1461-1468) of food intake.This result has the behavior hint, cause anxiety neurosis (Dunn etc. (1990) Brain Res.Brain Res.Rev.15:71-100) in the animal brain because CRF is administered to, and think that chronic stress plays pivotal role (Chrousos (2000) Int.J.Obes.Relat.Metab.Disord.24:S50-S55 with active raising of relevant maincenter CRF in the generation of clinical depression and anxiety neurosis; Koob (1999) Biol.Psychiatry 46:1167-1180).Therefore, as if the pancreas opsonin influences known mediation behavior state stress path as the maincenter of depressed and anxiety, and can be used as therapeutic agent and treat these diseases.
In order to confirm to carry out various animal behaviors and test the anxiety of pancreas opsonin administration, antidepressant and psychosis effect according to the explanation of the discovery of embodiment 1 general introduction.Art-recognized animal model is used in the performance testing of carrying out, and this model proves characteristic features and so display surface validity of clinical disease (for example, anxiety neurosis, depression, schizophrenia, obsession) separately.Known these specificity performance testings are responsive to anxiety, antidepressant or antipsychotic drug.For these tests, with rat pancreas opsonin with 0.1 to 10mg/kg dosed administration in mice, intraperitoneal or contain the osmotic pumps (ALZET ) of carrier or rat pancreas opsonin, and measure their performances in test by subcutaneous implantation.
The hyperpyrexia of stress-induced
In the mankind, body temperature is closely related with emotional state, and thinks that the hyperpyrexia (SIH) of stress-induced has predictive validity for specific people's anxiety neurosis/stress disorders in the mice.The SIH measurements determination antianxiety drugs or test medicament to effect that stress inductive hyperpyrexia and measure the intrinsic effect of these medicines to the animal core temperature.Referring to, for example, Zethof etc. (1994) Physiol.Behav.55:109-115.Fervescence or hyperpyrexia that antianxiety drugs weakens after stress exposing are replied.Before test 60 minutes with rat pancreas opsonin (0.1,1.0 or 10mg/kg) or contrast medicament (carrier or 10mg/kg chlordiazepoxide) treatment animal.Mice is accepted two continuous rectal temperatures measurements of ten minutes at interval.From the stress-induced of first measurement hyperpyrexia, measure by the temperature survey second time.Difference (Δ T) between two temperature is the hyperpyrexia of stress-induced.The results are shown among Fig. 2, wherein of this test
*P＜0.05.As shown in Figure 2, administration pancreas opsonin, the same with antianxiety drugs positive control chlordiazepoxide (CDP), weakened SIH and replied.The SIH test result has proved the anxiety activity of pancreas opsonin administration.Also test with 300 μ g/kg/d slow administration pancreas opsonins and with animals received SIH by the pump of subcutaneous implantation.In 1 week and 4 weeks of administration, chronic pancreas opsonin is inculcated and is significantly slowed down SIH and reply, and it is the same that gentle flood irrigation is failed CDP10mg/kg/d.
Pellet shot from a slingshot is buried (Marble burying)
Pellet shot from a slingshot is buried as anxiety neurosis and compulsive model.Referring to, for example, Chaki etc. (2003) J.Pharmacol.Exp.Titer.304:818-826.Antianxiety drugs suppresses the marbleburying activity.Before test 15-30 minute to injected in mice test medicament (0.1,1.0 or the rat pancreas opsonin of 10mg/kg, 20/kg buspirone, or carrier).Be placed in the clean cage mice is single then, contain the hardwood bed of 5-cm in the cage and on average in five rows place 20 pellets shot from a slingshot.Write down the quantity of the pellet shot from a slingshot of burying in 30 minutes.The results are shown among Fig. 3, wherein of this test
*P＜0.05.As shown in Figure 3, the administration of pancreas opsonin, the same with antianxiety drugs positive control buspirone, reduced the quantity of the pellet shot from a slingshot of burying.The minimizing of pellet shot from a slingshot being buried with the buspirone of the pancreas opsonin of 10mg/kg and 20mg/kg is significant statistically.Buspirone is part 5-HT1A agonist and known antianxiety drugs.Pellet shot from a slingshot is buried the active and anti-obsession activity of anxiety that test result has proved the administration of pancreas opsonin.
The forced swimming test
Forced swimming test (FST) is a usual usage paradigm of estimating the medicine antidepressant activity.This test is based on the animal measurement of the flotation time in filling the groove of water.When forcing rat or mice to swim in containing the dark cylinder of warm water, they become to be close to motionless and to stop trial and run away.Think that the motionless state response of this characteristic goes out the influence that depressed sample state also is subjected to various antidepressant easily.Referring to, for example, Hedou etc. (2001) Pharmacol, Biochem.Behav.70:65-76, (1977) Nature 266:730-732 such as (2003) J.Pharmacol.Exp.Ther.304:818-826 such as Chaki and Porsolt.Antidepressant reduces the dead time among the FST.Before FST, send rat pancreas opsonin or continuous two weeks of carrier to mice by subcutaneous implantable osmotic pump.At first day, before the swimming phase, mice was placed tank 15 minutes.At second day, mice is put in the return flume, be used for estimating climbing, swimming and motionless 5 minute testing period.FST the results are shown among Fig. 4, wherein
*P＜0.05.As shown in Figure 4, the administration of rat pancreas opsonin has significantly reduced the time of motionless state cost.Therefore, FST result has proved the antidepressant activity of pancreas opsonin administration.
Suppress before the pulse
Suppress (PPI) thermometrically before the pulse (audition startle reaction) and relevant with the sense organ motion gate capability defect seen in the schizophrenia is replied in the reflection of the auditory stimulus of applications.The audition startle reflex is the very sense organ motor reaction of replying and being widely used in test animal and people on basis of external intereceptic stimulation.The feel hard of hearing that (120dB) gives before strong auditory stimulus stimulates that (prepulse 74-82dB) has weakened to startle and replys.This weakening of replying that startle is called the prepulse inhibition.Referring to, for example, Conti etc. (2005) BehavioralNeuroscience 119:1052-1060.Psychosis improves prepulse and stimulates the ability that startling of intense stimulus replied that weakens.In fact some psychomimeticss as phencyclidine (PCP) and ketamine, can reduce in the animal prepulse and suppress percentage ratio and stimulate psychosis sample state, and this can resist by major tranquilizer.
15 with injected in mice test agent (0.1,1.0 or the rat pancreas opsonin of 10mg/kg, or carrier) or at test injection in preceding 30 minutes 1mg/kg haloperidol before test.Mice is placed animal holder and holder is placed on the platform of sound chamber.(120dB) gives feel hard of hearing before strong auditory stimulus stimulates (prepulse) 74,78 and 82dB.The record animal is to " reaction " amount of strong stimulation.The results are shown among Fig. 5, wherein of PPI test
*P＜0.05.As shown in Figure 5, the pancreas opsonin of administration 10mg/kg, the same with psychosis positive control haloperidol, the prepulse that significantly improves the prepulse level (74,78 and 82dB) of all tests suppresses percentage ratio.Haloperidol is dopamine-receptor antagonist and first generation psychosis.The PPI test result has proved the psychosis effect of pancreas opsonin administration.
Phencyclidine (PCP)-inductive motion
The recreation room and motion, raising and the mechanical activity of measurement under the inductive condition of amphetamine/PCP-in open place used in the inductive test of PCP-.The hyperkinesia that test is seen with amphetamines and PCP for some normalizations and the psychosis of stereotyped behavior have predictive validity.Referring to, for example, Williams etc. (2006) Prog.Neuropsychopharmacol.Biol.Psychiatry 30:239-243.Before injection 5mg/kg PCP 15-30 minute to injected in mice test medicament (0.1,1.0 or the rat pancreas opsonin of 10mg/kg, 3mg/kg clozapine (CZP), or carrier).Then animal was placed the center in open place and record movable 60 minutes.The results are shown among Fig. 6, wherein of this test
*It is P＜0.05.As shown in Figure 6, the administration of pancreas opsonin, CAP is the same with the psychosis positive control, has significantly reduced total distance (total, maincenter and periphery) that all types measured in the inductive animal testing of PCP passes.The pancreas opsonin, the same with CZP, reduce raising activity and the inductive raising activity of PCP.The individually dosed not influence basis of pancreas opsonin is movable, and CPZ has influenced basic activity separately.CZP is atypical second filial generation psychosis, has the blended body characteristics that is subjected to, and comprises dopamine receptor.CZP has good antipsychotic activity, has lower kinematic pair effect.The inductive exercise test result of PCP has proved the antipsychotic activity of pancreas opsonin administration.
Detected the effect of the weight increase that the administration of pancreas opsonin causes second filial generation psychosis clozapine.Transmit the osmotic pumps in carrier or 4 weeks of medicine continuously for the subcutaneous implantation in bull Sprague-Dawley rat (meals=58%kcal is from fat) position between omoplate.In one embodiment, handle rat with carrier or clozapine (0.025 and 0.25mg/kg/ days).In second experiment, handle rat in conjunction with rat pancreas opsonin (10g/kg/ days) with clozapine (0.25mg/kg/ days) or clozapine (0.25mg/kg/ days).Fig. 7 A has shown with the rat of vehicle treated and has compared, the weight increase that the rat that clozapine is handled is improved.When Fig. 7 B had shown pancreas opsonin and clozapine co-administered, the pancreas opsonin had prevented with observed weight increase in the rat of clozapine individual processing.
Although description before discloses the present invention, the embodiment that provides is used for illustrative purposes, understands variation, adaptation or change that practice of the present invention comprises that all are commonly used, as in desired scope of the present invention.Therefore, description and embodiment should not thought to limit the scope of the invention, scope of the present invention is described by claims.
Claims (12)
1. treat psychosis or patient with phychlogical problems's method, described method comprises that pancreas opsonin, amylin agonist, pancreas opsonin analog or the pancreas opsonin derivant with treatment disease or obstacle effective dose delivers medicine to the patient of needs, wherein said disease or obstacle are dysthymic disorder, anxiety neurosis or schizophrenia, and wherein said amylin agonist is not a calcitonin.
2. according to the process of claim 1 wherein that described amylin agonist is not calcitonin-gene-related peptide (CGRP).
3. according to the process of claim 1 wherein that described disease or obstacle are anxiety neurosis.
4. according to the method for claim 3, wherein said anxiety neurosis is an obsession.
5. according to the process of claim 1 wherein that described disease or obstacle are depressions.
6. according to the process of claim 1 wherein that described disease or obstacle are schizophrenia.
7. according to the process of claim 1 wherein that described method also comprises at least a other psychotherapeutic drugses are delivered medicine to the patient.
8. the treatment patient is from the method for the side effect of psychosis medicine, and described method comprises that pancreas opsonin, amylin agonist, pancreas opsonin analog or the pancreas opsonin derivant that will alleviate side effect symptom effective dose deliver medicine to the patient of needs.
9. method according to Claim 8, wherein said side effect are weight increase, diabetes or unusual lipidemia.
10. according to the method for claim 9, wherein said psychotherapeutic drugs is a second filial generation psychosis.
11. be used for the method for patient's mental disorder, described method comprises that pancreas opsonin, amylin agonist, pancreas opsonin analog or the pancreas opsonin derivant with treatment obstacle effective dose delivers medicine to the patient of needs, wherein said mental disorder is the material associated disorders, and wherein amylin agonist is not a calcitonin.
12. according to the method for claim 11, wherein said material associated disorders is the inductive obstacle of substance addiction or material.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104271596A (en) * | 2012-01-26 | 2015-01-07 | 克里斯托弗·J·索尔斯 | Peptide antagonists of the calcitonin CGRP family of peptide hormones and their use |
| CN112494637A (en) * | 2020-12-08 | 2021-03-16 | 中山大学附属第七医院(深圳) | Application of salmon calcitonin in preparation of medicines for treating depression |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104271596A (en) * | 2012-01-26 | 2015-01-07 | 克里斯托弗·J·索尔斯 | Peptide antagonists of the calcitonin CGRP family of peptide hormones and their use |
| CN104271596B (en) * | 2012-01-26 | 2018-09-18 | 克里斯托弗·J·索尔斯 | The purposes of the peptide antagonists and they of the calcitonin C GRP families of peptide hormone |
| CN108997490A (en) * | 2012-01-26 | 2018-12-14 | 克里斯托弗·J·索尔斯 | The purposes of the peptide antagonists of the calcitonin C GRP family of peptide hormone and they |
| US10370425B2 (en) | 2012-01-26 | 2019-08-06 | Christopher Joseph Soares | Peptide antagonists of the calcitonin CGRP family of peptide hormones and their use |
| CN112494637A (en) * | 2020-12-08 | 2021-03-16 | 中山大学附属第七医院(深圳) | Application of salmon calcitonin in preparation of medicines for treating depression |
| CN112494637B (en) * | 2020-12-08 | 2023-05-23 | 中山大学附属第七医院(深圳) | Application of salmon calcitonin in preparation of medicament for treating depression |
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