Use of the receptor GPR86

• US 20070248545A1
• Filed: 12/21/2006
• Published: 10/25/2007
• Est. Priority Date: 07/01/2004
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Messager, Sophie, Dixon, John, Malinge, Isabelle, Carlton, Mark, Hendrick, Alan, Brice, Nicola, Zahn, Dirk
• Granted Patent: US 7,879,564 B2
• Time in Patent Office: Days
• US Class Current: 424/9.200
• CPC Class Codes: A01K 2217/075 inducing loss of function, i.e. knock out
• CPC Class Codes: A01K 2227/105 Murine
• CPC Class Codes: A01K 2267/0356 Animal model for processes and diseases of the central nervous system, e.g. stress, learning, schizophrenia, pain, epilepsy
• CPC Class Codes: A01K 67/0276 Knock-out vertebrates
• CPC Class Codes: A61K 49/0008 Screening agents using (non-human) animal models or transgenic animal models or chimeric hosts, e.g. Alzheimer disease animal model, transgenic model for heart failure
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: C07K 14/70571 for neuromediators, e.g. serotonin receptor, dopamine receptor
• CPC Class Codes: C12N 15/8509 for producing genetically modified animals, e.g. transgenic
• CPC Class Codes: G01N 2333/726 G protein coupled receptor, e.g. TSHR-thyrotropin-receptor, LH/hCG receptor, FSH
• CPC Class Codes: G01N 2500/00 Screening for compounds of potential therapeutic value
• CPC Class Codes: G01N 2800/24 Immunology or allergic disorders
• CPC Class Codes: G01N 2800/52 Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/566 using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
• CPC Class Codes: G01N 33/6893 related to diseases not provided for elsewhere

Abstract

We describe a method of identifying a molecule suitable for the treatment, prophylaxis or alleviation of a GPR86 associated disease, in particular inflammatory disease or pain, the method comprising determining whether a candidate molecule is an agonist or antagonist of GPR86 polypeptide, in which the GPR86 polypeptide comprises the amino acid sequence shown in SEQ ID NO: 3 or SEQ ID NO: 5 or SEQ ID NO: 7, a fragment thereof or a sequence which is at least 90% identical thereto.

Claims

1. A method of identifying a compound capable of binding to GPR86 polypeptide, the method comprising:

(a) contacting a GPR86 polypeptide with a candidate compound; and

(b) determining whether the candidate compound binds to the GPR86 polypeptide;

wherein the compound is suitable for treating, preventing or alleviating inflammatory disease or pain in an individual, wherein the inflammatory disease or pain is associated with activity of GPR86.

2. The method of claim 1, wherein the GPR86 polypeptide comprises an amino acid sequence shown in SEQ ID NO:

3 or SEQ ID NO;

5 or SEQ ID NO;

7 or a sequence having at least 90% sequence identity thereto.

3. The method of claim 1, wherein the compound is an agonist or an antagonist of GPR86 polypeptide.

4. The method of claim 1, wherein the compound is an antibody.

5. The method of claim 1, wherein the candidate compound is exposed to a cell expressing a GPR86 polypeptide.

6. The method of claim 5, wherein the GPR86 polypeptide is coupled to G_i and a decrease in intracellular cyclic AMP (cAMP) concentration is detected, thereby identifying an agonist of GPR86.

7. The method of claim 5, wherein the GPR86 polypeptide is coupled to G_i and an increase in intracellular cyclic AMP (cAMP) concentration is detected, thereby identifying an antagonist of GPR86.

8. The method of claim 5, wherein the GPR86 polypeptide is coupled to a promiscuous stimulatory G-protein and an increase in intracellular cyclic AMP (cAMP) concentration is detected, thereby identifying an agonist of GPR86.

9. The method of claim 5, wherein the GPR86 polypeptide is coupled to a promiscuous stimulatory G-protein and a decrease in intracellular cyclic AMP (cAMP) concentration is detected, thereby identifying an antagonist of GPR86.

10. The method of claim 1, wherein the pain is selected from the group consisting of:

acute pain, chronic pain, cutaneous pain, somatic pain, visceral pain, referred pain, myocardial ischaemia, phantom pain, pain arising from injuries, diseases, headaches, migraines, cancer pain, pain arising from neurological disorders, pain arising from spine and peripheral nerve surgery, brain tumors, traumatic brain injury (TBI), spinal cord trauma, chronic pain syndromes, chronic fatigue syndrome, neuralgia, pain arising from lupus, sarcoidosis, arachnoiditis, arthritis, rheumatic disease, period pain, back pain, lower back pain, joint pain, abdominal pain, chest pain, labour pain, musculoskeletal and skin diseases, head trauma, and fibromyalgia.

11. The method of claim 10, wherein the neuralgia is selected from the group consisting of trigeminal neuralgia, glossopharyngeal neuralgia, postherpetic neuralgia and causalgia.

12. The method of claim 1, wherein the inflammatory disease is selected from the group consisting of rheumatoid arthritis, multiple sclerosis, Guillain-Barre syndrome, Crohn'"'"'s disease, ulcerative colitis, psoriasis, graft versus host disease, systemic lupus, erythematosus or insulin-dependent diabetes mellitus, autoimmune disease, acute pain, chronic pain, neuropathic pain, contact dermatitis, atherosclerosis, glomerulonephritis, reperfusion injury, bone resorption diseases, asthma, stroke, myocardial infarction, thermal injury, adult respiratory distress syndrome (ARDS), multiple organ injury secondary to trauma, dermatoses with acute inflammatory components, acute purulent meningitis, necrotising enterocolitis, syndromes associated with hemodialysis, septic shock, leukopherisis, granulocyte transfusion, acute or chronic inflammation of the lung caused by smoke inhalation, endometriosis, Behcet'"'"'s disease, uveitis, ankylosing spondylitis, pancreatitis, cancer, Lyme disease, restenosis following percutaneous transluminal coronary angioplasty, Alzheimer'"'"'s disease, traumatic arthritis, sepsis, chronic obstructive pulmonary disease, congestive heart failure, osteoporosis, cachexia, Parkinson'"'"'s disease, periodontal diseases, gout, allergic diseases, age-related macular degeneration, infection and cystic fibrosis.

13. The method of claim 12, wherein the autoimmune disease is selected from the group consisting of toxic shock syndrome, osteoarthritis, diabetes and inflammatory bowel disease.

14. A method of identifying a compound suitable for treating, preventing or alleviating inflammatory disease or pain comprising:

(a) administering a candidate compound capable of binding to GPR86 polypeptide to an animal, and

(b) determining whether the animal exhibits (i) increased or decreased sensitivity to pain, or (ii) increased or decreased susceptibility to inflammatory pain, as compared with an animal to which the candidate compound has not been administered;

thereby identifying a compound for treating, preventing or alleviating inflammatory disease or pain.

15. The method of claim 14, wherein the GPR86 polypeptide comprises an amino acid sequence shown in SEQ ID NO:

3 or SEQ ID NO;

5 or SEQ ID NO;

7 or a sequence having at least 90% sequence identity thereto.

16. The method of claim 14, wherein the animal expresses functional GPR86 polypeptide.

17. The method of claim 14, wherein the animal is a wild type animal.

18. The method of claim 14, wherein the animal is a rodent.

19. The method of claim 14, wherein the animal is a mouse.

20. The method of claim 14, wherein the (i) increased or decreased sensitivity to pain, or (ii) increased or decreased susceptibility to inflammatory pain is determined using a tail flick test, a formalin test, a Von Frey hair test or a neuropathic pain test.

21. The method of claim 14, further comprising:

(c) administering the compound capable of binding to GPR86 polypeptide to an animal that does not express functional GPR86 polypeptide; and

(d) determining whether the compound produces side effects in the animal.

22. The method of claim 21, wherein the side effects are selected from the group consisting of:

changes to disease resistance;

altered inflammatory response, altered tumour susceptibility;

a change in blood pressure;

neovascularization;

a change in eating behavior;

a change in body weight;

a change in bone density;

a change in body temperature;

a change in insulin secretion;

a change in gonadotropin secretion;

a change in nasal and/or bronchial secretion;

vasoconstriction;

loss of memory;

anxiety;

hyporeflexia;

hyperreflexia; and

changes in pain or stress responses, compared with an animal that does not express functional GPR86 polypeptide to which the compound is not administered.

23. A method of identifying an antagonist of GPR86 polypeptide, the method comprising:

(a) administering a candidate compound capable of binding to GPR86 polypeptide to an animal; and

(b) determining whether the animal exhibits (i) decreased sensitivity to pain or (ii) decreased susceptibility to inflammatory pain, as compared with a wild type animal to which the candidate compound has not been administered,

thereby identifying an antagonist of GPR86 polypeptide.

24. A method of identifying an agonist of GPR86 polypeptide the method comprising:

(a) administering a candidate compound capable of binding to GPR86 polypeptide to an animal; and

(b) determining whether the animal exhibits (i) increased sensitivity to pain, or (ii) increased susceptibility to inflammatory pain, as compared with a wild type animal to which the candidate compound has not been administered,

thereby identifying an agonist of GPR86 polypeptide.

25. A method of treating an individual suffering from inflammatory disease or pain, wherein the inflammatory disease or pain is associated with GPR86 activity, the method comprising administering a modulator of GPR86 to the individual.

26. A method of diagnosing susceptibility to inflammatory disease or pain in an individual, wherein the inflammatory disease or pain is associated with GPR86 activity, the method comprising detecting a change in expression pattern or level of GPR86 in a cell or tissue of the individual.

27. A method of diagnosing susceptibility to inflammatory disease or pain in an individual, wherein the inflammatory disease or pain is associated with GPR86 activity, the method comprising detecting a polymorphism in a GPR86 polynucleotide in a cell or tissue of the individual.

28. The method of claim 31, wherein the GPR86 polynucleotide comprises a nucleic acid sequence shown in SEQ ID NO:

1, SEQ ID NO;

2, or SEQ ID NO;

4.

29. A transgenic non-human mammal comprising a disruption in the endogenous GPR86 gene, wherein the disruption results in a change in a biological parameter selected from the group consisting of response to stimuli, response to heat, response to light, an immune response, an inflammatory response, and response to pain, as compared to a wild type animal.

30. A cell or tissue isolated from the transgenic non-human mammal of claim 29.