CN102614514A - GLP-1 acceptor agonists used for treating pains - Google Patents
GLP-1 acceptor agonists used for treating pains Download PDFInfo
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Abstract
The invention relates to glucagon-like peptide-1 (GLP-1) acceptor agonists (comprising: macromolecular agonists, such as GLP-1 and derivatives thereof, and exendins and derivatives thereof; and micromolecular agonists, such as geniposides) used for treating diseases, such as pains, especially chronic pains, comprising neuropathic pains, cancer pains, diabetic pains, immune inflammation pains, pains in back and loin, and the like which can be treated through activating a central nervous system comprising a spinal cord GLP-1 acceptor.
Description
Technical field
The present invention relates to glucagon-like-peptide-1 (glucogan-like peptide-1, GLP-1) receptor stimulating agent is used to treat pain, especially chronic pain specifically to the agonism of GLP-1 receptor in the nervous system; Also relate to the method for utilizing the GLP-1 receptor to identify medicament.
Background technology
Pain is one of modal symptom clinically, and a lot of diseases or disease all pain symptom can occur, and have a strong impact on patient's quality of life, and treatment pain has become in health care and the disease treatment one of factors of considerations at most.Therefore pain has obtained the increasing concern of the world of medicine, and 2000-2010 has been called as the pain age.Pain is offending sensation and the emotional experience that is associated with acute or potential disorganization, impels people to avoid or said destruction situation, thereby protects health and avoid destructive further generation.Most of pain disappear after pain stimulation is eliminated immediately, have eliminated and health obviously recovers but pain still continues although stimulate sometimes.In addition, although detect less than any stimulation, destruction or disease sometimes, but still pain appears.Based on this, pain can be divided into acute pain and chronic pain.
Chronic pain is the focus of current international pain research, and is different according to the reason that takes place, can be divided into inflammation pain, neuropathic pain, tumor (cancer) bitterly, diabetes pain and lumbago and backache etc.The difference of chronic pain and acute pain is it not exclusively is some non-infringement sexual stimuluses that the peripheral nerve irriate causes, as touch, severe pain that stimulation such as warm also can cause diseased region.Chronic pain is everlasting and is damaged the generation of back a period of time, and this pain has spontaneity, randomness and persistency, and also how invalid take analgesic commonly used, and often cannot be cured all one's life.Chronic pain relates to complicated formation mechanism; The ectopic discharge of periphery and maincenter sensitization (central sensitization) are that the chronic pain of extensively approving at present comprises the main mechanism (Basbaum et al.Cell139:267-284,2009) that neuropathic pain and relaxing tumor pain form.The chronic pain sickness rate is higher, total account for crowd's 10%, and increase and to prolong with the protopathy journey and to increase (can reach 13% like sickness rate more than 55 years old, be 8% at the diabetes diagnosis initial stage for another example, and can be up to 50% after diagnosing 25 years) with the age.
Pain (comprising cancer pain, neuropathic pain etc. like various forms of chronic pains) treatment insufficient in ward, intensive care unit (ICU), emergency treatment etc. ubiquity.Medicament, psychotherapy, physiotherapy and traditional medicine therapy are waited treat pain.For example, can use medicines such as analgesics and anesthetis to come management of acute pain.Comparatively speaking, the treatment of chronic pain will be stranded much more difficult, possibly need many-sided joint efforts just can reach result relatively preferably.
Treat chronic pain at present clinically and mainly comprise tricyclics such as amitriptyline (amitriptyline); Antuepileptic such as gabapentin and lyrica; Local anesthetic such as lignocaine (Lidocaine); Opiates medicine (like morphine, Dilauid, fentanyl and buprenorphine), adrenoceptor blocker such as clonidine, and 5-HT reuptake inhibitor such as duloxetine and ziconotide etc.But because the cognition degree lower to chronic pain, on the market existing most products specially to chronic pain, invalid or can only appropriate alleviating pain to most of patient, maybe can cause many untoward reaction, or administration is inconvenient.Inconsistent like each family's report of morphine treatment neuropathic pain; The amitriptyline untoward reaction is more for another example, comprises postural hypotension, urine retention, vagueness in memory, myocardium conduction abnormalities, drowsiness etc.; Spinal cord is injected ziconotide and is used inconvenience for another example.Drug therapy chronic pain success rate is limited at present in a word.Therefore the novel anti chronic pain medicine of seeking safe and effective, no addiction property, convenient use is that the whole world has greatly challenging key subjects.
Drucher in 1987 etc. detect the bind receptor (GLP-1 receptor) of glucagon-like-peptide-1 (GLP-1) in rat Langerhans islet oncocyte RIN1046-38; But its clone equals completion (Thorens in 1992 by Thorens; Proc.Natl.Acad.Sci., 89:8641-8645,1992).Subsequently, (Nishizawa et al., J.Auton.Nerv.Syst., 80:14221,2000 of existing of this receptor in people's islets of langerhans, brain, spinal cord, lung, stomach, small intestinal, kidney and heart tissue, have all been found; Tibaduiza et al., J.Biol.Chem., 276:37787-37793; 2001), but in the main peripheral tissues (like liver, skeletal muscle and fatty tissue) of glucose metabolism, do not find it and have (Montrose et al., J.Cell Physiol.; 172:275-283,1997; Yang et al., Am.J.Physiol., 275:C675-C683,1998).The DNA cross experiment shows that the GLP-1 acceptor gene is positioned at the 6p21 of human chromosome, and genome total length 40kd has 7 exons at least.The GLP-1 receptor of people and rat all contains 463 aminoacid, and homology is 91%; The receptor protein of mice has 489 aminoacid, with people's GLP-1 receptor homolog property be 84%.
The GLP-1 receptor belongs to the glucagon receptor subfamily in the g protein coupled receptor B family (secretin family).The obvious characteristics of this subfamily is the relatively long outer N terminal sequences of born of the same parents, forms a globular domain through three disulfide bond.This zone has many glycosyl modified, in the part cohesive process, plays a crucial role, and finds itself to be not sufficient to combine with part but this domain is separated the back.In fact; Pass through the complex space conformation that the interaction between the particular amino acid residue forms between born of the same parents outer region and 7 TMDs, part is combined also to have risen certain function (Tibaduiza et al., J.Biol.Chem.; 276:37787-37793,2001).Mutation analysis shows that the charge residue of aminoterminal and extracellular region is extremely important to its function, and the 3rd born of the same parents' internal ring of acceptor control 5 and the 6th TMD is relevant with the G albumen coupling.Up to the present, do not found that the function mutation of this receptor was relevant with the susceptibility of diabetes or other diseases.
The major physiological function of present known GLP-1 receptor mainly comprises the following aspects:
1. the function in islet cells:
1) promote secretion of insulin: the GLP-1 receptor belongs to the Gs subclass in the g protein coupled receptor, and is responsive to cholera toxin.Behind the classical agonist GLP-1 and receptors bind of GLP-1 receptor, link coupled G protein alpha subunit and β, γ subunit dissociation, and mediate various signals path in the born of the same parents respectively.In the beta Cell of islet model; After the G alpha subunit is activated, stimulate adenyl cyclase, cause rising of cAMP level and PKA activation in the cell; Cause a series of cascade reactions, comprise ion channel activity change, intracellular Ca2+ rheologyization, the release of insulin secretion vesicle etc.GLP-1 directly improves the sensitivity of beta Cell of islet to glucose through the cAMP-PKA approach, stimulates the dependent insulin continuous release of blood glucose (Holz et al., J.Biol.Chem., 274:14147-14156,1999).Glucose metabolism makes ATP concentration increase in the cell, and the ratio of ATP and ADP raises, and impels ATP dependency potassium-channel to close; The cell membrane depolarization; L type calcium channel is opened on the film, and further promotes intracellular calcium store to discharge calcium ion, promotes the excretion vesicles of insulin-containing to efflux.The promoting insulin secretion of GLP-1 is tangible glucose dependency, when concentration of glucose is lower than 4.5mM, does not have any reaction; Simultaneously, this effect is again omnibearing, influences each function links such as proinsulin gene transcription, translation and montage.In addition, with the closely-related gene of carbohydrate metabolism, like glucokinase and GLUT 2, its expression is all raised by GLP-1 in the β cell.But also there are some researches show the mode that the insulin gene promoter in the rat β cell can part rely on PKA be activated (Bode et al., Endocrinology, 140:3919-3927,1999).2) stimulate the β proliferation of cells: after the GLP-1 receptor is activated; G albumen β, γ subunit are induced the propagation and differentiation (the Leech et al. of β cell through the signal path that phosphatidylinositol-3-kinase (P13K) and silk split first activated protein kinase (MAPK); Biochem.Biophys.Res.Commun.; 278:44-47,2000).3) apoptosis of inhibition β cell: express through raising Akt1 gene, Prosurvival kinases and p44MAPK, reduce Caspase-3 active (Wang et al., Diabetologia, 45:1263-1273,2002).4) reduce glucagon secretion, concrete molecular mechanism is still not clear at present.
2. the effect in nervous tissue:
The GLP-1 receptor all has expression in hypothalamus, brain stem and XIAONAO, point out it in brain, to have certain physiological function.GLP-1 gets into brain through blood circulation, and the low-density that all can detect iodine mark GLP-1 at the neuron of cerebral cortex, Hippocampus and XIAONAO combines, but the GLP-1 receptor is undiscovered so far at the endogenic ligand of brain.In isolated experiment, GLP-1 can promote the differentiation of neuronal cell, and its function class is similar to nerve growth factor, but relevant signalling channel is still waited to illustrate.There are some researches show that recently GLP-1 suppresses appetite and the food ration of rat with the dose dependent mode, and exendin (9-39) can reverse this phenomenon (Meeran et al., Endocrinology, 140:244-250,1999).Equally, no matter in the normal person still is diabetics, uses GLP-1 and all can make it produce of short duration full feeling to feel and appetite decline.Relevant with diet control because of thalamic nuclei, this zone has the GLP-1 expression of receptor again, and the GLP-1 of supposition periphery might affect indirectly nervus centralis through the signal transmission and produce full sense, reduces appetite.As stated, the generation of cAMP is most important to GLP-1 signal conduction, but and the rising neuroprotective unit of cAMP avoids apoptosis; Although the present existing darker understanding of The mechanism of apoptosis, the link that possibly involve therein for the GLP-1 receptor is systematic study not as yet, there is data to show; PI3K relies on and MAPK dependent/non-dependent signal pathway has been played the part of important role (Hui et al. at this; Endocrinology, 144:1444-1455,2003).
3. to the influence of gastrointestinal function:
Find that in a series of researchs GLP-1 can suppress gastrointestinal motility and gastric secretion, postpone gastric emptying (Meier et al., J.Clin.Endocrinol.Metab., 88:2719-2725,2003) Mus, pig and people.
4. to the effect of cardiovascular system:
GLP-1 to action of the heart main with its increase cell in cAMP content, promote stream in the calcium, and relevant at the content of cardiac muscle and activation PKA and downstream signal path anti-myocardial apoptosis through effect pyruvic dehydrogenase effect minimizing acetone acid.
At present use maximum GLP-1 receptor antagonists to be exendin (9-39), be mainly used in (Goke et al., J.Biol.Chem., 268:19650-19655,1993 such as biological action of checking GLP-1 receptor; Furuse et al., Japanese Poultry Science, 35:376-380,1998).Present known GLP-1 receptor stimulating agent mainly comprises macromole such as peptide class and micromolecule two big classes.
1. peptide class: 1) GLP-1 (Mojsov et al., J.Biol.Chem., 261:11880-11889,1986; Nathan et al., Diabetes Care, 15:270-276,1992) and derivant such as liraglutide, GTP-010 etc.; 2) exendin-4/exenatide (Goke et al., J.Biol.Chem., 268:19650-19655,1993) and derivant thereof etc.The exendin-4 preparation that injection in a day of the common exploitation of next (Eli Lilly) company of existing U.S. peace Milin (Amylin) and gift is twice (exenatide, trade name: Byetta) in listing (United States Patent (USP) 5,424,286,6 in 2005; 858,576,6,872,700; 6,902,744,6,956; 026,7,297,761) treatment type ii diabetes.In addition, Liraglutide has gone through in 2009 to go on the market and has been used to treat type ii diabetes.
2. micromolecule agonist, as: 1) Boc5 (SH7870) and S4P (SH7871) (Chen et al., Proc.Natl.Acad.Sci., 104:943-948,2007) and derivant thereof are positive configuration agonist, and its biological action can be blocked by exendin (9-39); 2) " Compound 2 " (quinoxalines) and derivant (Knudsen et al., Proc.Natl.Acad.Sci., 104:937-942,2007; Teng et al., Bioorg.Med.Chem.Lett., 17:5472-5478,2007), it is other configuration regulator, biological action is not blocked by exendin (9-39); 3) " Compound A " and " Compound B " (pyrimidine) and derivant be other configuration agonist, biological action is by exendin (9-39) blocking-up (Sloop et al., Diabetes59:3099-3107,2010); 4) geniposide (Liu et al., Neurochem.Int., 51:361-369,2007); 5) ZYOG1 has got into I phase clinical research treatment type ii diabetes and obesity (the http://www.zyduscadila.com/press/PressNote21-06-10.pdf of Zydus Cadila company's site) at present; 6) T0632 (Kopin et al., WO2004/103310,2004); 7) " 6Cu compound " (Wang et al., Acta Pharmacologica Sinica 31:1026-1030,2010) etc.
The central nervous system especially GLP-1 receptor of spinal cord does not see any report as the target spot molecular studies of treatment pain.The present existing GLP-1 research relevant with pain has 3; The first comes from clinical research proof subcutaneous injection GLP-1 analog GTP-010 can reduce the pain that irritable bowel syndrome (Irritable Bowel Syndrome) produces, its effect and the relevant (WO2008/134425 of inhibition intestinal movement;
Regulatory Peptides 156:9-12,2009); It two is to come from the open WO2007/028394 of patent application, and this patent application discloses GLP-1 receptor agonist treatment biliary dyskinesia and biliary colic, its effect with suppress biliary tract and move relevant.The author thinks in this two example, and related pain is disorderly relevant with gi system power, and the GLP-1 receptor stimulating agent is to have removed pain through suppressing digestive tract power.Therefore, they all belong to because of the disorderly pain that causes of digestive tract power, and especially generation, development and the site of action of chronic pain have different mechanism with traditional pain.Doctor Matwyshyn that the 3rd research about the influence of GLP-1 receptor and pain comes from Midwestern University is in AAPSAnnual Meeting and Exposition meeting of holding in 2009 and the meeting report on 2010 world's pharmacology conference (WorldPharm2010) subsequently; But his conclusion of report is that the continuous drug administration by injection in GLP-1 receptor stimulating agent exendin-4 abdominal cavity can not produce analgesic activity; Morphine analgesic activity and tolerance thereof also there is not influence (Matwyshyn et al.; AAPS-002278,2009).
Summary of the invention
The inventor is surprised to find that; The GLP-1 receptor stimulating agent can activate the especially GLP-1 receptor among central nervous system's (comprising spinal cord) of nervous system; Thereby treatment can be through activating the disease that said GLP-1 receptor obtains medical treatment, like pain, and chronic pain especially.
Therefore, in one aspect, present disclosure provides a kind of treatment can be through activating the method for the disease that said GLP-1 receptor obtains medical treatment, comprising giving the GLP-1 receptor stimulating agent that has this object that needs to use effective dose.
In one embodiment, said can be pain through activating the disease that said GLP-1 receptor obtains medical treatment, especially chronic pain.In a specific embodiments, said disease is not the pain that the digestive tract power disorder causes.
In a specific embodiments, saidly can be selected from chronic pain through activating the disease that said GLP-1 receptor obtains medical treatment, neuropathic pain, chronic low back pain, headache; Migraine, trigeminal neuralgia, cluster headache, FMS, arthralgia; Inflammatory pain, arthritis ache, osteoarthritis pain, rheumatoid arthritis pain, relaxing tumor pain; Cancer pain, Encelialgia, somatalgia, musculoskeletal pain, osteodynia; Lumbosacral pain, cervicodynia or upward backache, the pain that diabetic pain, spinal cord injury cause, operation pain; Postoperative pain, acute pain, or the pain relevant with infection, sicklemia, autoimmune disease, multiple sclerosis or inflammation, by the pain of damaging or operation causes, or their combination.
In another embodiment, said can being selected from and following relevant pain: diabetic neuralgia, peripheral neuralgia, postherpetic neuralgia, the radiculalgia of waist or neck, fibromyalgia through activating the disease that said GLP-1 receptor obtains medical treatment; Glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, phantom pain; Pain after the thoracotomy, cancer, chemical damage, toxin, malnutrition, virus or bacterial infection; Temporomandibular joint disturbance syndrome, FMS, osteoporosis, the osteodynia that bone shifts or other unknown causes cause, gout; Fibrositis, myofascial pain, thoracic outlet syndrome, backache or lumbago, pelycalgia; Cardiac chest pain, non-cardiac chest pain, spinal cord injury dependency pain, pain after the central apoplexy, cancer pain; The AIDS pain, antitumor drug causes neuralgia, meniscocyte's pain, old pain, or their combination.
In another embodiment, said GLP-1 receptor stimulating agent can be macromole GLP-1 receptor stimulating agent or micromolecule GLP-1 receptor stimulating agent.For example said macromole GLP-1 receptor stimulating agent includes but not limited to GLP-1, liraglutide, GTP-010, exendin-4 (exenatide), exendin-3 and other exendins, and functional variant, fragment, derivant and analog.Said macromole GLP-1 receptor stimulating agent can have modification or not have modification, and said modification for example is to put together the structure (moeity) of increase molecular weight such as PEG or albumin to prolong the biological activity of said GLP-1 receptor stimulating agent.Said functional variant for example comprises various GLP-1 variants or exendin variant.For example said micromolecule GLP-1 receptor stimulating agent includes but not limited to genipin and derivant geniposide and Geniposidic acid; Boc5 (SH 7870); S4P (SH7871), " Compound 2 " (quinoxalines) and derivant (Knudsen et al., Proc.Natl.Acad.Sci.; 104:937-942,2007; Teng et al., Bioorg.Med.Chem.Lett., 17:5472-5478,2007); " Compound A " and " Compound B " (pyrimidine) and derivant (Sloop et al., Diabetes 59:3099-3107,2010); ZYOG1, T0632, " 6Cu Compound " (Wang et al.; Acta Pharmacologica Sinica 31:1026-1030,2010), and derivant.
In one embodiment, administered through oral or parenteral approach are used said GLP-1 receptor stimulating agent, for example comprise subcutaneous injection, and spinal cord is used, and intracranial is used, intramuscular injection, and via intranasal application is used, and intravenous administration and/or intraperitoneal are used.
In another embodiment, said method also comprises to said object uses other pain therapy agent, and for example said pain therapy agent includes but not limited to: analgesics such as opioid analgesic; Anti-inflammatory agent, migraine preparation, tricyclics; Antuepileptic; Alpha-2 receptor agonist, or selective serotonin reuptake inhibitor/selectivity norepinephrine uptake inhibitors, or their combination.
In a specific embodiments, said other pain therapy agent is selected from morphine class medicine (like morphine, Dilauid, fentanyl, buprenorphine and uncle's fourth coffee), gabapentin; Lyrica; Ziconotide, Luo Xiting, clonidine; Lignocaine; DAO enzyme inhibitor (like 5-chlorobenzene also [d] isoxazole-3-alcohol, AS057278, sodium benzoate, 3-hydroxyquinoline-2-(1H)-ketone and 4H-thieno [3,2-b] pyrroles-5-carboxylic acid), and the nmda receptor blocker (like MK-801, ketamine, dextromethorphan, phencyclidine and (2R)-amino-5-phosphine valeric acid.
In second aspect; Present disclosure also provides the GLP-1 receptor stimulating agent to be used for treating in preparation can be through activating the especially purposes in the medicine of the central nervous system GLP-1 receptor disease that obtain medical treatment of nervous system; Said disease is pain preferably, especially chronic pain.In the various embodiments of said purposes, especially comprise and the corresponding technical scheme of related each embodiment of above-mentioned first aspect Therapeutic Method.
In the third aspect, present disclosure also provides the GLP-1 receptor stimulating agent, and it is used for treatment can be through activating the especially disease that obtains medical treatment of central nervous system GLP-1 receptor of nervous system, and said disease is pain preferably, especially chronic pain.In the various embodiments of the said GLP-1 receptor stimulating agent that is used for treating, especially comprise and the corresponding technical scheme of related each embodiment of above-mentioned first aspect Therapeutic Method.
In addition; In fourth aspect; Present disclosure also provides a kind of method of identifying the medicament that treatment can be through activating the disease that the GLP-1 receptor obtains medical treatment in the nervous system; It comprises: test compounds is provided, said test compounds is contacted with GLP-1 receptor (like GLP-1 receptor on the neurocyte) and measures the activity of said GLP-1 receptor; If said test compounds can improve the activity of GLP-1 receptor, so said test compounds can be used as treatment can be through activating the medicament of the disease that the GLP-1 receptor obtains medical treatment in the nervous system.In one embodiment, said disease is a pain, especially chronic pain.
In fourth aspect, present disclosure also provides the medicament that a kind of use identifies according to above-mentioned authentication method and uses the medicament of being identified to treat the method for the disease that can obtain medical treatment through GLP-1 receptor in the activation nervous system.In one embodiment, said disease is a pain, chronic pain especially, the various pain of for example mentioning more than the present disclosure.
The patent system of considering country variant has different regulations to the protection theme, and present disclosure also provides and corresponding pharmaceutical applications of above method and the medicine that is used for intended purpose.These various pharmaceutical applications and medicine are also in protection domain of the present invention, just as they are specifically put down in writing in this disclosure.
Only for example clear some specific embodiments that require protection of present disclosure; The technical characterictic of being put down in writing in one of them or the more a plurality of technical scheme can be with one or more technical schemes be combined arbitrarily; These technical schemes that obtain through combination are also in the application's protection domain, just as the concrete in this disclosure record of these technical schemes that obtain through combination.
To combine accompanying drawing and following further detailed description to illustrate the present invention.It is pointed out that following explanation only is to the illustrating of the technical scheme of requirement of the present invention protection, is not any restriction to these technical schemes.Protection scope of the present invention is as the criterion with the content of appended claims record.
Description of drawings
Fig. 1 illustrates, pancreas in rat, spinal cord, dorsal root ganglion, cerebral cortex and GLP-1 Receptor mRNA.Use real-time PCR method, organize repetition 3 times for every kind.
Fig. 2 illustrates, and pancreas in rat (A) and spinal cord (B) GLP-1 receptor immunologic opsonin dyeing (pale brown color) distribute.
Fig. 3 illustrates, spinal cord injection GLP-1 receptor peptide excitomotor exenatide (A) and GLP-1 (7-36) and (B) micromolecule agonist geniposide (C), Geniposidic acid (D) and genipin (E) cause the influence of pain model to rat formalin.Calculate the dose-effect relationship (F) of medicine with TG-AUC to II phase pain reaction.
Fig. 4 illustrates, and spinal cord injection GLP-1 receptor stimulating agent exenatide carries out dose-effect relationship according to 1 hour pain threshold after the administration and calculates (C) the inhibitory action of rat bone cancer pain model (A) and neuropathic pain model (B).
Fig. 5 illustrates, and subcutaneous injection gives GLP-1 receptor peptide excitomotor exenatide inhibitory action to mice formalin pain.
Fig. 6 illustrates, subcutaneous injection and the influence of filling stomach GLP-1 receptor micromolecule agonist geniposide to mice formalin pain.
Fig. 7 illustrates, and continuous 7 days subcutaneous injection exeantide and geniposide are to mice formalin I pain (A) and the II influence of pain (B) mutually mutually.Compare with normal saline+normal saline matched group,
aRepresent P＜0.05; Compare with normal saline+morphine group,
bRepresent P＜0.05.
Fig. 8 illustrates, and spinal cord injection GLP-1 receptor antagonist exendin (9-39) blocking-up GLP-1 receptor stimulating agent is to the inhibitory action of rat formalin pain.Spinal cord injection GLP-1 receptor antagonist exendin (9-39) blocking-up exenatide, GLP-1 (7-36) and geniposide (A, C) to the inhibitory action of rat formalin pain and formalin II mutually pain TG-AUC AUC (B, D).Compare with corresponding normal saline group,
aRepresent P＜0.05; Compare with corresponding exenatide, GLP-1 (7-36) and geniposide group,
bRepresent P＜0.05.
Fig. 9 illustrates, and GLP-1 receptor antagonist exendin (9-39) is to the influence of subcutaneous injection geniposide analgesic activity.Compare with the normal saline matched group,
aRepresent P＜0.05; Compare with the geniposide group,
bRepresent P＜0.05.
The specific embodiment
Used like present disclosure; Term " treatment " is meant through medical intervention and makes the target disease of treating treatment target or disease and/or its any symptom and/or its any possible complication and/or sequela obtain effecting a radical cure, eliminate, alleviate, improve, stop aggravation and/or prevention, perhaps makes and treat any good effect on that treatment target obtains to take place immediately and/or the potential medical significance.
Used like present disclosure, term " agonist " thereby be meant can combine and the active cell receptor brings out this cell and produces the chemical substance of replying.Term " GLP-1 receptor stimulating agent " is meant the material that can combine and activate the GLP-1 receptor, and they can be induced and produce and the similar biological effect of GLP-1.It is pointed out that GLP-1 itself is also included within the GLP-1 receptor stimulating agent.In addition, when mentioning the GLP-1 receptor stimulating agent, its implication not only comprises having this active chemical compound, its solvate, hydrate and salt form, also comprises the forms such as prodrug of said agonist.
The inventor is surprised to find that; The GLP-1 receptor stimulating agent can activate the especially GLP-1 receptor among central nervous system's (comprising spinal cord) of nervous system; Thereby treatment can be through activating the disease that said GLP-1 receptor obtains medical treatment, like pain, and chronic pain especially.
Therefore, in one aspect, present disclosure provides a kind of treatment can be through activating the method for the disease that said GLP-1 receptor obtains medical treatment, comprising giving the GLP-1 receptor stimulating agent that has this object that needs to use effective dose.
In one embodiment, said can be pain through activating the disease that said GLP-1 receptor obtains medical treatment, especially chronic pain.In a specific embodiments, said disease is not the pain that the digestive tract power disorder causes.
In a specific embodiments, saidly can be selected from chronic pain through activating the disease that said GLP-1 receptor obtains medical treatment, neuropathic pain, chronic back pain, headache; Migraine, trigeminal neuralgia, cluster headache, FMS, arthralgia; Inflammatory pain, arthritis ache, osteoarthritis pain, rheumatoid arthritis pain, relaxing tumor pain; Cancer pain, Encelialgia, somatalgia, musculoskeletal pain, osteodynia; Lumbosacral pain, cervicodynia or upward backache, the pain that diabetic pain, spinal cord injury cause, operation pain; Postoperative pain, acute pain, or the pain relevant with infection, sicklemia, autoimmune disease, multiple sclerosis or inflammation, by the pain of damaging or operation causes, or their combination.
In another embodiment, said can being selected from and following relevant pain: diabetic neuralgia, peripheral neuralgia, postherpetic neuralgia, the radiculalgia of waist or neck, fibromyalgia through activating the disease that said GLP-1 receptor obtains medical treatment; Glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, phantom pain; Pain after the thoracotomy, cancer, chemical damage, toxin, malnutrition, virus or bacterial infection; Temporomandibular joint disturbance syndrome, FMS, osteoporosis, the osteodynia that bone shifts or other unknown causes cause, gout, fibrositis; Myofascial pain, thoracic outlet syndrome, last back pain, low back pain, pelycalgia; Cardiac chest pain, non-cardiac chest pain, spinal cord injury dependency pain, pain after the central apoplexy, cancer pain; The AIDS pain, antitumor drug causes neuralgia, meniscocyte's pain, old pain, or their combination.
In another embodiment, said GLP-1 receptor stimulating agent can be macromole GLP-1 receptor stimulating agent or micromolecule GLP-1 receptor stimulating agent.For example said macromole GLP-1 receptor stimulating agent includes but not limited to GLP-1, liraglutide, GTP-010, exendin-4 (exenatide), exendin-3 and other exendins, and functional variant, fragment, derivant and analog.Said macromole GLP-1 receptor stimulating agent can have modification or not have modification, and said modification for example is to put together the structure (moeity) of increase molecular weight such as PEG or albumin to prolong the biological activity of said GLP-1 receptor stimulating agent.Said functional variant for example comprises various GLP-1 variants or exendin variant.For example said micromolecule GLP-1 receptor stimulating agent includes but not limited to genipin, geniposide and Geniposidic acid, Boc5, S4P; " Compound 2 " (quinoxalines) and derivant (Knudsen et al.; Proc.Natl.Acad.Sci., 104:937-942,2007; Teng et al., Bioorg.Med.Chem.Lett., 17:5472-5478,2007); " Compound A " and " Compound B " (pyrimidine) and derivant (Sloop et al., Daibetes 59:3099-3107,2010); ZYOG1, T0632, " 6Cu Compound " (Wang et al.; Acta Pharmacologica Sinica 31:1026-1030,2010), and derivant.
In one embodiment, administered through oral or parenteral approach are used said GLP-1 receptor stimulating agent, for example comprise subcutaneous injection, and spinal cord is used, and intracranial is used, intramuscular injection, and via intranasal application is used, and intravenous administration and/or intraperitoneal are used.
In another embodiment, said method also comprises to said object uses other pain therapy agent, and for example said pain therapy agent includes but not limited to: analgesics such as opioid analgesic; Anti-inflammatory agent, migraine preparation, tricyclics; Antuepileptic; Alpha-2 receptor agonist, or selective serotonin reuptake inhibitor/selectivity norepinephrine uptake inhibitors, or their combination.
In a specific embodiments, said other pain therapy agent is selected from morphine class medicine (like morphine, Dilauid, fentanyl, buprenorphine and uncle's fourth coffee), gabapentin; Lyrica; Ziconotide, Luo Xiting, clonidine; Lignocaine; The DAO enzyme inhibitor (like 5-chlorobenzo [d] isoxazol-3-ol, AS057278, sodium benzoate, 3-hydroxyquinolin-2-(1H)-one and 4H-thieno [3,2-b] pyrrole-5-carboxylicacid, nmda receptor blocker (like MK-801, ketamine, dextromethorphan, phencyclidine and (2R)-amino-5-phosphonovaleric acid).
In second aspect; Present disclosure also provides the GLP-1 receptor stimulating agent to be used for treating in preparation can be through activating the especially purposes in the medicine of the central nervous system GLP-1 receptor disease that obtain medical treatment of nervous system; Said disease is pain preferably, especially chronic pain.In the various embodiments of said purposes, especially comprise and the corresponding technical scheme of related each embodiment of above-mentioned first aspect Therapeutic Method.
In the third aspect, present disclosure also provides the GLP-1 receptor stimulating agent, and it is used for treatment can be through activating the especially disease that obtains medical treatment of central nervous system GLP-1 receptor of nervous system, and said disease is pain preferably, especially chronic pain.In the various embodiments of the said GLP-1 receptor stimulating agent that is used for treating, especially comprise and the corresponding technical scheme of related each embodiment of above-mentioned first aspect Therapeutic Method.
In addition; In fourth aspect, present disclosure also provides a kind of method of identifying drug candidate, and it comprises: test compounds is provided; Said test compounds is contacted with GLP-1 receptor (like GLP-1 receptor on the neurocyte) and measure the activity of said GLP-1 receptor; If said test compounds can improve the activity of GLP-1 receptor, so said test compounds can be used as treatment can be through activating the drug candidate of the disease that the GLP-1 receptor obtains medical treatment in the nervous system.In one embodiment, said disease is a pain, especially chronic pain.
Pain can be divided into acute pain and chronic pain.The employed subcutaneous injection formalin of present disclosure causes rest pain (chronic pain, II phase reaction), and the osteocarcinoma injection cell is gone into rat tibia can cause rat Ipsilateral foot mechanical hyperalgesia (hyperalgesia); The neurogenic Ipsilateral foot mechanical hyperalgesia that the spinal nerves ligation causes, its function Characteristics all relates to maincenter sensitization (Coderre et al.Pain 54:43-50,1993; Jett et al.Pain 69:161-169,1997; Yanagisawaet al.Mol Pain 2010; 6:38-50,2010).Be not limited to any theory, the pain described in the present disclosure comprises the chronic pain that turns to characteristic with the maincenter sensitivity.
The GLP-1 receptor stimulating agent can be divided into macromole GLP-1 receptor stimulating agent and micromolecule GLP-1 receptor stimulating agent, and wherein macromole GLP-1 receptor stimulating agent mainly comprises peptide class GLP-1 receptor stimulating agent.
1. peptide class: 1) GLP-1 (Mojsov et al., J.Biol.Chem., 261:11880-11889,1986; Nathan et al., Diabetes Care, 15:270-276,1992) and derivant such as liraglutide, GTP-010 etc.; 2) exendin class is like exendin-4/exenatide (Goke et al., J.Biol.Chem., 268:19650-19655,1993) and derivant thereof etc.The exendin-4 preparation that injection in a day of the common exploitation of next (Eli Lilly) company of existing U.S. peace Milin (Amylin) and gift is twice (exenatide, trade name: Byetta) in listing (United States Patent (USP) 5,424,286,6 in 2005; 858,576,6,872,700; 6,902,744,6,956; 026,7,297,761) treatment type ii diabetes.Liraglutide has also gone through in 2009 to go on the market and has been used to treat type ii diabetes in addition.The interior half-life of the body of these peptide classes GLP-1 receptor stimulating agent is shorter usually, often needs repeat administration at short notice.Attempt multiple strategy and prolonged these peptide excitomotors activity in vivo.For example, improve the ability of these peptide opposed body endoproteinases (comprising peptidase, especially DPP IV (DPP IV)) degradeds, perhaps resist the ability of other Degradation (like oxidation etc.) through the aminoacid sequence that changes these peptides.Also attempted on these peptides, puting together the structure that increases molecular weight (like the PEG of albumin and/or various molecular weight etc.), this also can increase the half-life in the body of peptide excitomotor, thereby prolongs its biological activity.Had open and other non-patent literature of a large amount of patents to disclose these in the prior art and prolonged the method for GLP-1 receptor stimulating agent activity in vivo and have active GLP-1 receptor stimulating agent in the extension body through this modification, they are all in the scope of said in this disclosure GLP-1 receptor stimulating agent.
2. micromolecule agonist, as: 1) Boc 5 and S4P (Chen et al., Proc.Natl.Acad.Sci., 104:943-948,2007) and derivant thereof are positive configuration agonist, and its biological action can be blocked by exendin (9-39); 2) " Compound 2 " (quinoxalines) and derivant (Knudsen et al., Proc.Natl.Acad.Sci., 104:937-942,2007; Teng et al., Bioorg.Med.Chem.Lett., 17:5472-5478,2007), it is other configuration regulator, biological action is not blocked by exendin (9-39); 3) " Compound A " and " Compound B " (pyrimidine) and derivant is other configuration agonist, and biological action is by exendin (9-39) blocking-up (Sloop et al., Daibetes 59:3099-3107,2010); 4) geniposide (Liu et al., Neurochem.Int., 51:361-369,2007); 5) ZYOG1 has got into I phase clinical research treatment type ii diabetes and obesity (Zydus Cadila company's site) at present; 6) T0632 (Kopin et al., WO2004/103310,2004); 7) " 6Cu compound " (Wang et al., Acta Pharmacologica Sinica 31:1026-1030,2010) etc.
Up to now, the central nervous system especially in the spinal cord GLP-1 receptor do not see any report as the research of pain therapy target molecules.The inventor is surprised to find that, the GLP-1 receptor stimulating agent can act on the especially GLP-1 receptor among central nervous system's (comprising spinal cord) of nervous system, thereby realizes the effect of treatment pain.
We carry out analgesic activities research in the body to these GLP-1 receptor stimulating agents; Find that spinal cord and the subcutaneous GLP-1 of giving receptor stimulating agent comprise GLP-1; Exenatide, genipin and derivant geniposide thereof and Geniposidic acid can effectively suppress the inductive chronic pain of formalin (II phase reaction), relaxing tumor pain and neuropathic pain in dose dependent ground.Irritate the stomach geniposide in addition and also can effectively ease pain, the active bio availability is hypodermic 83.5%.Give the exenatide maximal percentage inhibition up to 70-80%, spinal cord and subcutaneous median effective dose ED
50Can hang down respectively and reach 0.5pmol/ rat and 5.4nmol/kg, possibly be present known strong analgesics thing.The more important thing is, opposite with morphine, gave exenatide continuously on 7th and geniposide does not produce toleration, for GLP-1 receptor agonist treatment chronic pain provides pharmacological basis.Spinal cord injection GLP-1 (7-36), exenatide and geniposide, Geniposidic acid and genipin suppress the inductive chronic pain ED of rat formalin in addition
50Be respectively 0.5pmol/ rat, 1.2pmol/ rat, 63.0nmol/ rat, 43nmol/ rat and 85nmol/ rat, it is relevant that their exciting GLP-1 receptor actives are positivity.The analgesic activity of GLP-1 (7-36), exenatide and geniposide all can be blocked by the GLP-1 receptor antagonist exendin (9-39) of spinal cord injection fully simultaneously; Proof activate the central nervous system especially in the spinal cord GLP-1 receptor can produce effective analgesic activity, the GLP-1 receptor is the target spot molecule of treatment pain.
The present invention will further specify through following examples, and it should not be interpreted as the restriction to protection domain of the present invention by any way.The full content of the list of references of all references among the application (patent, disclosed patent application and the co-pending patent application of comprise the article reference, authorizing) is all incorporated this paper clearly by reference into.In following examples, if do not specifically note, agents useful for same and material are can the commercial analytical pure at least that obtains or suitable therewith other product of level.The expression of EXAMPLE Example 1 rat spinal cord GLP-1 receptor (GLP-1 receptor) mRNA
Male Wistar rat (Shanghai Si Laike laboratory animal responsibility company limited) is with pentobarbital sodium (60mg/kg) (Sigma; Shanghai, China) anesthesia, expose its thoracic cavity; Carry out cardiac perfusion with normal saline; Expand position and cerebral cortex to getting pancreas in rat, skeletal muscle, neuroganglion, lumbar spinal cord after systemic blood flows to end, put into ready 1.5ml centrifuge tube, and labelling.
The GLP-1 acceptor gene is expressed according to the 100mg tissue and is added 1ml Trizol reagent (Invitrogen, Shanghai, China), adds the Trizol reagent of respective volume.Quality according to OD260/OD280 and the definite RNA that extracts of nucleic acid electrophoresis.Use reverse transcriptase (Toyobo, Japan spin (Shanghai) bio tech ltd),, under corresponding reverse transcription condition, the total RNA reverse transcription of 1 μ g is become cDNA according to manufacturer's explanation.The cDNA that produces with reverse transcription is a template; With GAPDH is confidential reference items; With quantitative fluorescent PCR (Mastercycler ep realplex real-time PCR system, Eppendorf, Hamburg; Germany) detect each position genes of interest GLP-1 expression of receptor of rat, change with 2-Δ Δ Ct methods analyst genes of interest GLP-1 expression of receptor.3 rat experiment results are as shown in Figure 1; Pancreas in rat ability high expressed GLP-1 receptor; Spinal cord GLP-1 expression of receptor amount is about 16.8% of pancreas; Neuroganglion and cerebral cortex GLP-1 expression of receptor amount are respectively 1.1% and 1.3% of pancreas a little less than, and skeletal muscle almost detects less than GLP-1 receptor expression (0.04%).Embodiment 2 rat spinal cords and pancreas GLP-1 receptor immunohistochemistry specific stain distribute
Male Wistar rat (Shanghai Si Laike laboratory animal responsibility company limited) is with pentobarbital sodium (60mg/kg) (Sigma; Shanghai, China) anesthesia, expose its thoracic cavity; Carry out cardiac perfusion with normal saline; Expand the position to getting pancreas in rat, skeletal muscle, neuroganglion and lumbar spinal cord after systemic blood flows to end, put into that 4% paraformaldehyde is fixing to dewater after 24 hours and transparent, FFPE, 5 μ m section, section dewaxing, section is placed 30%H
2O
2/ formalin (1: 9) soaking at room temperature 15 minutes is with the activity of deactivating endogenous peroxydase, with PBST flushing 3 times, each 2 minutes; Be heated to boiling in the sodium citrate buffer solution (pH6.0) with section immersion 0.01M, 10 minutes at interval, repeat 2 times; Unnecessary liquid is got rid of with PBST washing 2 times in cooling back, Dropwise 5 %BSA confining liquid, room temperature 20 minutes, get rid of unnecessary liquid after; Drip the GLP-1 receptor one anti-(1: 500, ab39072, Abcam, Cambridge, USA) 4 ℃ of incubated overnight; PBST washes 3 times, and each 5 minutes, goat anti-rabbit igg-HRP (1: 2000, SA00001-2, ProteintechGroup; Inc., Chicago USA) was hatched 20 minutes for 37 ℃, and PBST washes 3 times, each 5 minutes; Drip sABC (SA1022, Wuhan Boster Biological Technology Co., Ltd.) 37 ℃ and hatched 20 minutes, PBST washing 4 times; Each 5 minutes, get rid of unnecessary liquid, the DAB colour developing; Distilled water wash after 15 minutes carries out hematoxylin and slightly redyes, and the neutral gum mounting is used in dehydration, transparent back; Take pictures with optical microscope after 24 hours, get 5,10,20 and 40 times of mirror visual field undertissues respectively and carry out interpretation of result.The dyeing of GLP-1 receptor-specific mainly is distributed in beta Cell of islet (Fig. 2 A) in pancreas, in skeletal muscle, do not see (not shown).GLP-1 receptor-specific dyeing (pale brown color) all has distribution at each layer of rat spinal cord, but mainly is distributed in the intermediate layer of grey matter and white matter, is positioned at (Fig. 2 B) on the cell membrane.The also visible a small amount of GLP-1 receptor-specific dyeing (not shown) of neuroganglion.Embodiment 3 spinal cord injection GLP-1 receptor peptide excitomotor exenatide and GLP-1 (7-36) and micromolecule agonist geniposide, Geniposidic acid and genipin cause the influence of pain model to rat formalin
Male Wistar rat (200～250g) every groups 4 of body weight.Cause preceding 30 minutes of pain respectively intrathecal injection 10 μ l/ rat normal saline, exenatide (1,3,10,30 with 100ng/ rat, the triumphant prompt biological medicine in Chengdu technology & development Co.), GLP-1 (7-36) (1 at formalin; 3,10,30 with the 100ng/ rat, Shanghai peptide bodyguard bio tech ltd), geniposide (3; 10,30,100 and 300 μ g/ rats, Nanjing Zelang Pharmaceutical Technology Inc.), Geniposidic acid (3; 10,30,100 and 300 μ g/ rats, the letter bio tech ltd in Linchuan) and genipin (3; 10,30,100 and 300 μ g/ rats, the letter bio tech ltd in Linchuan).The right back instep of rat is injected 50 μ l, 5% formalin and is caused pain, between 0-90 after the formalin injection minute, every in observation in ten minutes 1 minute rat lift foot or tremble the foot number of times as the pain index.Experimental result is as shown in Figure 3; Spinal cord injection GLP-1 receptor peptide excitomotor exenatide (Fig. 3 A) and GLP-1 (7-36) (Fig. 3 B), micromolecule agonist geniposide (Fig. 3 C), Geniposidic acid (Fig. 3 D) and genipin (Fig. 3 E) all are dosage dependence formula and suppress formalin chronic pain (II phase reaction); Calculate with TG-AUC; Maximal percentage inhibition is for being respectively 69.8%, 60.1%, 57.2%, 63.7% and 66.4%; ED
50Value is respectively 2.0ng/ rat (0.5pmol/ rat), 3.8ng/ rat (1.2pmol/ rat), 24.4 μ g/ rats (63.0nmol/ rat), 16.1 μ g/ rats (43nmol/ rat) and 19.2 μ g/ rats (85nmol/ rat) (Fig. 3 F).
Behavior observation show give GLP-1 receptor stimulating agent such as GLP-1 (7-36), exenatide, geniposide, Geniposidic acid and genipin do not have evident act learn change as calm, shake, paralyse, enrage, movable increasing, explain that it produces sedation or motor coordination function impaired and generation to the GLP-1 receptor stimulating agent non-specificly no thanks to the analgesic activity of pain.Embodiment 4 spinal cord injection GLP-1 receptor peptide excitomotor exenatide are to the inhibitory action of rat bone cancer pain model and neuropathic pain model
(5 μ l rat Walker, 256 cell suspension (1 * 10 are injected in the boring at 0.5cm place under shin bone to female Sprague Dawley rat (150～180g, Shanghai Si Laike laboratory animal responsibility company limited) for 50mg/kg, i.p.) anesthesia with pentobarbital sodium
7Individual cell/ml, cell resource center of Shanghai Sheng Ke institute of the Chinese Academy of Sciences) in medullary cavity.Operation back was chosen the successful bone cancer pain rat of modeling on the 14th day, detected mechanicalness pain sensation threshold value, and rat is performed the operation, and to be regarded as the modeling of osteocarcinoma pain less than 8g successful for sufficient mechanicalness pain sensation threshold value.Choose the successful bone cancer pain rat of modeling; Divide 6 groups: normal saline (10 μ l/ rat); 3,10,30,100 and 300ng/ rat exenatide dose groups (n=4), detect before the administration and the variation of the mechanicalness threshold of pain of 0.5,1,2,4 hour time point after the administration.Experimental result is shown in Fig. 4 A; The rat Ipsilateral foot mechanicalness threshold of pain is tangible dose-effect relationship and time-effect relationship; Spinal cord injection exenatide does not influence the normal limbs mechanicalness of rat pain sensation threshold value; But suppress Ipsilateral foot mechanicalness pain sensation threshold value, the persistent period, 4 hours mechanicalness threshold of pains began to reduce after the administration more than 2 hours.Carry out dose-effect relationship according to 1 hour pain threshold after the administration and calculate, exenatide is dosage dependence formula and suppresses bone cancer pain hyperpathia, and (%Maximum Possible Effect is 55.6% %MPE) to maximum possible analgesic effect, ED
50Be 10.5ng/ rat (2.5pmol/ rat) (Fig. 4 C).
Male Wistar rat (body weight 150-170g), animal conformed 3 days.With pentobarbital sodium (50mg/kg, i.p.) anesthetized rat.Spinal cord inserts the PE-10 conduit and expands the place to the spinal column marrow in the ilium position, and rats with left is carried out the ligation of L5/L6 spinal nerves.Treat that rat recovered after 3～7 days, (California USA) detects rats with left sole mechanicalness pain sensation threshold value for Electronic von Frey Anesthesiometer, IITC Life Science Inc. to use IITC CE220; Select the rat of left side mechanicalness pain sensation threshold value, be the successful rat of modeling less than 8g.Choose the successful neuropathic pain rat of modeling; Divide 6 groups: normal saline (10 μ l/ rat); 3,10,30,100 and 300ng/ rat exenatide dose groups (n=4), detect before the administration and the variation of the mechanicalness threshold of pain of 0.5,1,2,4 hour time point after the administration.Experimental result is shown in Fig. 4 B; The rat Ipsilateral foot mechanicalness threshold of pain is tangible dose-effect relationship and time-effect relationship; Spinal cord injection exenatide does not influence the normal limbs mechanicalness of rat pain sensation threshold value; But suppress Ipsilateral foot mechanicalness pain sensation threshold value, the persistent period, 4 hours mechanicalness threshold of pains began to reduce after the administration more than 2 hours.Carry out dose-effect relationship according to 1 hour pain threshold after the administration and calculate, exenatide is dosage dependence formula and suppresses neuropathic pain hyperpathia, and (%Maximum Possible Effect is 54.3% %MPE) to maximum possible analgesic effect, ED
50Be 11.3ng/ rat (2.7pmol/ rat) (Fig. 4 C).Embodiment 5 subcutaneous injections give GLP-1 receptor peptide excitomotor exenatide inhibitory action to mice formalin pain
Male Swiss mice (freely drink water, take food, and is divided into 5 groups, 4 every group by body weight 20～25g).Formalin cause preceding 30 minutes 5 groups of mices of pain respectively subcutaneous injection give 10ml/kg normal saline and exenatide (10,30,100 and 300 μ g/kg).The right back instep of mice is injected 10 μ l, 5% formalin and is caused pain, and 0-5 minute (I phase reaction) and 20-40 minute (II phase reaction) mice continue to lick the foot time as the pain index after the observation formalin injection.Experimental result shows that the subcutaneous exenatide of giving is dosage dependence formula and suppresses formalin chronic pain (II phase reaction) (Fig. 5 A), and maximal percentage inhibition is 82.0%, ED
50Value is 22.7 μ g/kg (5.4nmol/kg) (Fig. 5 B).Embodiment 6 subcutaneous with irritate stomach and give of the influence of GLP-1 receptor micromolecule agonist geniposide mice formalin pain
Male Swiss mice (freely drink water, take food, and is divided into 7 groups, 3 every group by body weight 20～25g).Cause the preceding 30 minutes subcutaneous respectively 10ml/kg of giving normal saline of 7 groups of mices of pain and geniposide (3,10,30,100 and 300mg/kg) at formalin, and filling stomach (oral) gives geniposide (100mg/kg).Experimental result shows that the subcutaneous GLP-1 of giving receptor micromolecule agonist geniposide is dosage dependence formula and suppresses formalin chronic pain (II phase reaction) (Fig. 6 A), and maximal percentage inhibition is 71.5%, ED
50Value is 13.1mg/kg (Fig. 6 B).The filling stomach gives geniposide and also can effectively suppress mice formalin chronic pain (II phase pain) (Fig. 6 A).Irritate stomach and subcutaneous injection and give Isodose 100mg/kg geniposide, suppress II phase pain and be respectively 53.3% and 63.8%.With biological activity relatively, oral administration biaavailability is hypodermic 83.5% (Fig. 6 C).Embodiment 7 continuous 7 days subcutaneous injection exeantide and geniposide are to the influence of mice formalin pain
Male Swiss mice (freely drink water, take food, and is divided into 7 groups, 4 every group by body weight 20～25g).4 groups of mice difference subcutaneous injection normal saline (10ml/kg/ is each, every day 2 times), continuous 7 days.Difference subcutaneous single dose injecting normal saline (10ml/kg) after 12 hours, exenatide (100 μ g/kg), geniposide (100mg/kg) and morphine (5mg/kg); 3 groups of mice difference subcutaneous injection exenatide (100 μ g/kg/ are each, every day 2 times), geniposide (100mg/kg/ is each, every day 2 times) and morphine (10mg/kg/ is each, every day 2 times), continuous 7 days.Respectively subcutaneous single dose injection exenatide (100 μ g/kg) after 12 hours, geniposide (100mg/kg) and morphine (5mg/kg).The single dose injection is after 30 minutes, and the right back instep of mice is injected 10 μ l5% formalin and caused pain, and 0-5 minute (I phase reaction) and 20-40 minute (II phase reaction) mice continue to lick the foot time as the pain index after the observation formalin injection.Shown in Fig. 7 A and 7B, experimental result is illustrated in the control mice of continuous 7 days subcutaneous injection normal saline, and single dose injection exenatide all can suppress formalin II pain mutually with geniposide, and suppression ratio is respectively 65.0% and 67.5%; The single dose injection of morphine to formalin I phase pain and II mutually pain inhibitory action is all arranged, suppression ratio is respectively 84.8% and 100%.And continuous 7 days subcutaneous injection exeantide and geniposide do not produce toleration, single dose injection this moment exeantide and geniposide to formalin II mutually the pain suppression ratio be respectively 67.0% and 50.9%, with corresponding single dose inject contrast identical; Opposite continuous 7 days subcutaneous injection morphines produce obvious toleration, the single dose injection of morphine to formalin I phase pain and II mutually the suppression ratio of pain be respectively 12.2% and 12.4%.Embodiment 8 spinal cord injection GLP-1 receptor antagonist exendin (9-39) are to agonist exenatide, and GLP-1 (7-36) and geniposide suppress the influence of rat formalin pain
Male Wistar rat (freely drink water, take food, and is divided into 6 groups by body weight 200～250g).Cause preceding 30 minutes difference of pain intrathecal injection 10 μ l/ rat normal saline (n=4) at formalin; 30ng/ rat exenatide (n=4); 15 μ g/ rat exendin (9-39) (n=4); 100ng/ rat exendin (9-39)+30ng/ rat exenatide (n=3), 2 μ g/ rat exendin (9-39)+30ng/ rat exenatide (n=3) and 15 μ g/ rat exendin (9-39)+30ng/ rat exenatide (n=4).Cause pain model observation experiment index, the relation analysis of easing pain with reference to rat formalin.Experimental result is shown in Fig. 8 A and 8B, and spinal cord injection GLP-1 receptor peptide excitomotor exenatide (30ng/ rat) can effectively suppress formalin chronic pain (II phase reaction), and suppression ratio is 61.2%.Spinal cord injection GLP-1 receptor peptide agonist exendin (9-39) (15 μ g/ rat) does not influence rat formalin pain reaction (I mutually with II mutually).Exendin (9-39) (100ng/ rat) can not block the analgesic activity that exenatide (30ng/ rat) produces rat formalin II phase chronic pain, but reaches 2 μ g/ rats or can block the analgesic activity of exenatide (30ng/ rat) generation when above fully as exendin (9-39).
5 groups of male Wistar rats (body weight 200～250g), 4 every group.Cause preceding 30 minutes difference of pain intrathecal injection 10 μ l/ rat normal saline, 30ng/ rat GLP-1 (7-36), 2 μ g/ rat exendin (9-39)+30ng/ rat GLP-1 (7-36), 100 μ g/ rat geniposides and 2 μ g/ rat exendin (9-39)+100 μ g/ rat geniposides at formalin.Cause pain model observation experiment index, the relation analysis of easing pain with reference to rat formalin.Experimental result is shown in Fig. 8 C and 8D, and spinal cord injection GLP-1 (7-36) and geniposide all can effectively suppress formalin chronic pain (II phase reaction), and suppression ratio is respectively 57.0% and 57.3%.Spinal cord injection GLP-1 receptor peptide agonist exendin (9-39) (2 μ g/ rat) blocks the analgesic activity of GLP-1 (7-36) and geniposide fully.These results prove that exenatide, GLP-1 (7-36) and geniposide produce analgesic activity through exciting spinal cord GLP-1 receptor, and infer that geniposide is the positive configuration agonist of GLP-1 receptor.Embodiment 9GLP-1 receptor antagonist exendin (9-39) is to the influence of geniposide analgesic activity
Male Swiss mice (freely drink water, take food, and is divided into 4 groups, 4 every group by body weight 20～25g).Cause preceding 30 minutes subcutaneous respectively normal saline (10ml/kg) that give of 4 groups of mices of pain, geniposide (300mg/kg), exendin (9-39) (60 μ g/kg) and exendin (9-39) (60 μ g/kg)+geniposide (300mg/kg) at formalin.Cause pain model observation experiment index, the relation analysis of easing pain with reference to mice formalin.Experimental result is as shown in Figure 9, and subcutaneous injection GLP-1 receptor micromolecule agonist geniposide can effectively suppress formalin chronic pain (II phase reaction), and suppression ratio is 64.4%.Subcutaneous injection GLP-1 receptor peptide agonist exendin (9-39) (60 μ g/kg) does not influence rat formalin pain reaction (I mutually with II mutually); But can block the analgesic activity that geniposide produces mice formalin II phase chronic pain fully; Prompting exendin (9-39) can see through blood brain barrier blocking-up spinal cord GLP-1 receptor, and further proves the just exciting GLP-1 receptor in configuration ground and produce analgesic activity of geniposide.
Based on above content, it will be understood by those skilled in the art that technical scheme that the application requires to protect with and equivalent technical solutions will be conspicuous.In addition, those skilled in the art can also carry out suitable modification and change to disclosed technical scheme as required, and these modifications and improved technical scheme are also in the protection domain of the application's claims.
Claims (13)
1. the method for disease in the treatment target, wherein said disease can through activate nervous system especially among the central nervous system GLP-1 receptor obtain medical treatment, said method comprises the GLP-1 receptor stimulating agent of using effective dose to the object that these needs are arranged.
2. the process of claim 1 wherein that said disease is a pain, especially chronic pain.
3. claim 1 or 2 method, wherein said disease is not the pain that the digestive tract power disorder causes.
4. the method for aforementioned each claim, wherein said disease is selected from chronic pain, neuropathic pain, chronic low back pain, headache; Migraine, trigeminal neuralgia, cluster headache, FMS, arthralgia; Inflammatory pain, arthritis ache, osteoarthritis pain, rheumatoid arthritis pain, relaxing tumor pain; Cancer pain, Encelialgia, somatalgia, musculoskeletal pain, osteodynia; Lumbosacral pain, cervicodynia or upward backache, the pain that diabetic pain, spinal cord injury cause, operation pain; Postoperative pain, acute pain, or the pain relevant with infection, sicklemia, autoimmune disease, multiple sclerosis or inflammation, by the pain of damaging or operation causes, or their combination.
5. the method for aforementioned each claim, wherein said disease is selected from and following relevant pain: diabetic neuralgia, peripheral neuralgia, postherpetic neuralgia, the radiculalgia of waist or neck, fibromyalgia; Glossopharyngeal neuralgia, reflex sympathetic dystrophy, causalgia, thalamic syndrome, nerve root avulsion, phantom pain; Pain after the thoracotomy, cancer, chemical damage, toxin, malnutrition, virus or bacterial infection; Temporomandibular joint disturbance syndrome, FMS, osteoporosis, the osteodynia that bone shifts or other unknown causes cause, gout, fibrositis; Myofascial pain, thoracic outlet syndrome, last back pain, low back pain, pelycalgia; Cardiac chest pain, non-cardiac chest pain, spinal cord injury dependency pain, pain after the central apoplexy, cancer pain; The AIDS pain, antitumor drug causes neuralgia, meniscocyte's pain, old pain, or their combination.
6. the method for aforementioned each claim; Wherein said GLP-1 receptor stimulating agent is selected from macromole GLP-1 receptor stimulating agent and micromolecule GLP-1 receptor stimulating agent; For example said macromole GLP-1 receptor stimulating agent is selected from GLP-1, liraglutide, GTP-010; Exenatide (exendin-4); Exendin-3 and other exendins, and functional variant, fragment, derivant and analog, said macromole GLP-1 receptor stimulating agent can have modification or not have modification; Said modification for example is to put together the structure (moeity) of increase molecular weight such as PEG or albumin to prolong the biological activity of said GLP-1 receptor stimulating agent, and said functional variant for example comprises various GLP-1 variants or exendin variant; For example said micromolecule GLP-1 receptor stimulating agent is selected from geniposide and derivant Geniposidic acid and genipin, and Boc 5, S4P; " Compound 2 " (quinoxalines) and derivant (Knudsen et al.; Proc.Natl.Acad.Sci., 104:937-942,2007; Teng et al., Bioorg.Med.Chem.Lett., 17:5472-5478,2007); " Compound A " and " Compound B " (pyrimidine) and derivant (Sloop et al., Diabetes 59:3099-3107,2010); ZYOG1, T0632, " 6Cu Compound " (Wang et al.; Acta Pharmacologica Sinica 31:1026-1030,2010), and derivant.
7. the method for aforementioned each claim, wherein administered through oral or parenteral approach are used said GLP-1 receptor stimulating agent, for example comprise subcutaneous injection, and spinal cord is used, and intracranial is used, intramuscular injection, and via intranasal application is used, and intravenous administration and/or intraperitoneal are used.
8. the method for aforementioned each claim is wherein also used other pain therapy agent to said object, and for example said pain therapy agent is selected from: analgesics such as opioid analgesic; Anti-inflammatory agent, migraine preparation, tricyclics; Antuepileptic; Alpha-2 receptor agonist, or selective serotonin reuptake inhibitor/selectivity norepinephrine uptake inhibitors, or their combination.
9. the method for claim 8, wherein said other pain therapy agent is selected from morphine class medicine (like morphine, Dilauid, fentanyl, buprenorphine and uncle's fourth coffee), gabapentin; Lyrica; Ziconotide, Luo Xiting, clonidine; Lignocaine; The DAO enzyme inhibitor (like 5-chlorobenzo [d] isoxazol-3-ol, AS057278, sodium benzoate, 3-hydroxyquinolin-2-(1H)-one and 4H-thieno [3,2-b] pyrrole-5-carboxylicacid, nmda receptor blocker (like MK-801, ketamine, dextromethorphan and phencyclidine and (2R)-amino-5-phosphonovaleric acid).
10.GLP-1 receptor stimulating agent is used for treating in preparation can be through activating the especially purposes in the medicine of the central nervous system GLP-1 receptor disease that obtain medical treatment of nervous system, said disease is pain preferably, especially chronic pain.
11.GLP-1 receptor stimulating agent, it is used for treatment can be through activating the especially disease that obtains medical treatment of central nervous system GLP-1 receptor of nervous system, and said disease is pain preferably, especially chronic pain.
12. a method of identifying the medicament that treatment can be through activating the disease that the GLP-1 receptor obtains medical treatment in the nervous system, it comprises:
Test compounds is provided,
Said test compounds is contacted with the GLP-1 receptor and
Measure the activity of said GLP-1 receptor,
If said test compounds can improve the activity of GLP-1 receptor, so said test compounds can be used as treatment can be through activating the medicament of the disease that the GLP-1 receptor obtains medical treatment in the nervous system.
13. the method for claim 12, wherein said disease is a pain, especially chronic pain.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
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| CN201110028944.6A CN102614514B (en) | 2011-01-26 | 2011-01-26 | GLP-1 acceptor agonists used for treating pains |
| PCT/CN2012/070741 WO2012100748A1 (en) | 2011-01-26 | 2012-01-29 | Glp-1 receptor agonist for treating pain |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201110028944.6A CN102614514B (en) | 2011-01-26 | 2011-01-26 | GLP-1 acceptor agonists used for treating pains |
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| CN102614514B CN102614514B (en) | 2014-12-10 |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103536907A (en) * | 2013-07-18 | 2014-01-29 | 上海交通大学医学院附属瑞金医院 | Application of liraglutide in preparation of drug for treating osteoporosis |
| CN106729717A (en) * | 2016-12-12 | 2017-05-31 | 深圳市健翔生物制药有限公司 | The analogs of GLP 1 and ziconotide composition sustained-release microsphere preparation |
| CN109939119A (en) * | 2019-03-29 | 2019-06-28 | 山东省分析测试中心 | Application of the Gardenoside in preparation treatment multiple sclerosis agent |
| CN110051677A (en) * | 2019-01-11 | 2019-07-26 | 广东医科大学 | A kind of application of Gardenoside in terms of alleviating glucocorticoid side effect |
| CN113993514A (en) * | 2019-05-09 | 2022-01-28 | 穆罕默德·阿明·贾汉·帕纳 | Combination administration of diazepam and diclofenac for the treatment of pain |
| CN114984002A (en) * | 2022-07-25 | 2022-09-02 | 山西医科大学 | Application of compound of formula (I) in preparation of analgesic |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2994848B1 (en) * | 2012-08-30 | 2014-08-22 | Univ Paris Curie | TREATMENT OF ARTHROSIS BY INCRETINED HORMONES OR THEIR ANALOGUES |
| CN104994912A (en) * | 2012-12-06 | 2015-10-21 | 康肽德生物医药技术有限公司 | Peptide therapeutics and methods for using same |
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| CN1839870A (en) * | 2006-01-18 | 2006-10-04 | 刘建辉 | Use of geniposide as glicetin 1 acceptor excitomotor |
| WO2007028394A2 (en) * | 2005-09-08 | 2007-03-15 | Gastrotech Pharma A/S | Use of a glp-1 molecule for treatment of biliary dyskinesia and/or biliary pain/discomfort |
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| CN100531796C (en) * | 2002-01-31 | 2009-08-26 | 马普科技促进协会 | FGFR agonists |
| WO2007061434A2 (en) * | 2005-11-10 | 2007-05-31 | Nastech Pharmaceutical Company Inc. | A pharmaceutical formulation of glp-1 and its use for treating a metabolic syndrome |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2007028394A2 (en) * | 2005-09-08 | 2007-03-15 | Gastrotech Pharma A/S | Use of a glp-1 molecule for treatment of biliary dyskinesia and/or biliary pain/discomfort |
| CN1839870A (en) * | 2006-01-18 | 2006-10-04 | 刘建辉 | Use of geniposide as glicetin 1 acceptor excitomotor |
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| CN103536907A (en) * | 2013-07-18 | 2014-01-29 | 上海交通大学医学院附属瑞金医院 | Application of liraglutide in preparation of drug for treating osteoporosis |
| CN103536907B (en) * | 2013-07-18 | 2015-10-21 | 上海交通大学医学院附属瑞金医院 | The application of Arg34Lys26-(N-EPSILON-(N-ALPHA-Palmitoyl-L-GAMMA-glutamyl))-GLP-1[7-37] in osteoporosis therapy medicine |
| CN106729717A (en) * | 2016-12-12 | 2017-05-31 | 深圳市健翔生物制药有限公司 | The analogs of GLP 1 and ziconotide composition sustained-release microsphere preparation |
| CN110051677A (en) * | 2019-01-11 | 2019-07-26 | 广东医科大学 | A kind of application of Gardenoside in terms of alleviating glucocorticoid side effect |
| CN109939119A (en) * | 2019-03-29 | 2019-06-28 | 山东省分析测试中心 | Application of the Gardenoside in preparation treatment multiple sclerosis agent |
| CN109939119B (en) * | 2019-03-29 | 2021-09-21 | 山东省分析测试中心 | Application of geniposide in preparation of medicine for treating multiple sclerosis |
| CN113993514A (en) * | 2019-05-09 | 2022-01-28 | 穆罕默德·阿明·贾汉·帕纳 | Combination administration of diazepam and diclofenac for the treatment of pain |
| CN114984002A (en) * | 2022-07-25 | 2022-09-02 | 山西医科大学 | Application of compound of formula (I) in preparation of analgesic |
| CN114984002B (en) * | 2022-07-25 | 2023-11-17 | 山西医科大学 | Application of compound of formula (I) in preparing analgesic |
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| WO2012100748A1 (en) | 2012-08-02 |
| CN102614514B (en) | 2014-12-10 |
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