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1. (WO2007142979) USE OF GPR101 RECEPTOR IN METHODS TO IDENTIFY MODULATORS OF HYPOTHALAMIC PROOPIOMELANOCORTIN (POMC)-DERIVED BIOLOGICALLY ACTIVE PEPTIDE SECRETION USEFUL IN THE TREATMENT OF POMC-DERIVED BIOLOGICALLY ACTIVE PEPTIDE-RELATED DISORDERS
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CLAIMS

What is claimed is:

1. A method of identifying a candidate compound as a modulator of hypothalamic proopiomelanocortin (POMQ-derived biologically active peptide secretion, said method comprising:
(a) contacting the candidate compound with a recombinant host cell or membrane thereof that comprises a GPCR, wherein said receptor comprises an amino acid sequence selected from the group consisting of:
(i) the amino acid sequence of SEQ ID NO: 2;
(ii) the amino acid sequence of a G protein-coupled receptor encoded
by a polynucleotide that is amplifiable by polymerase chain reaction
(PCR) on a human DNA sample using specific primers SEQ ID
NO: 7 and SEQ ID NO: 8;
(iii) the amino acid sequence ofSEQ ID NO: 4;
(iv) the amino acid sequence of SEQ ID NO:6;
(v) the amino acid sequence of a G protein-coupled receptor encoded
by a polynucleotide hybridizing under stringent conditions to the
complement of SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5;
(vi) the amino acid sequence of a G protein-coupled receptor that has an
amino acid sequence having at least about 70% identity to SEQ ID
NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6;
(vii) the amino acid sequence of a G protein-coupled receptor having a
variant of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO:
4 or SEQ ID NO: 6; and
(viii) a biologically active fragment of any one of (i) to (vii);
wherein the receptor couples to a G protein; and
(b) deteπrώiing the ability of the compound to inhibit or stimulate functionality of the GPCR;
wherein the ability of the compound to inhibit or stimulate functionality of the GPCR is indicative of the compound being a modulator of hypothalamic proopiomelanocortin (POMC)-derived biologically active peptide secretion.

2. The method of claim 1, wherein the GPCR comprises the amino acid sequence of SEQ ID NO: 2 or the amino acid sequence of a G protein-coupled receptor that has an amino acid sequence having at least about 70% identity to SEQ ID NO: 2.

3. The method of claim 1 or claim 2, wherein the ability of the compound to stimulate functionality of the GPCR is indicative of the compound being a compound that stimulates hypothalamic proopiomelanocortin (POMC)-derived biologically active peptide secretion.

4. The method of any one of claims 1 to 3, wherein the POMC-derived biologically active peptide is selected from the group consisting of ACTH, j3-endorphin, αs-MSH, β-MSH and T-MSH.

5. The method of any one of claims 1 to 4, wherein the method comprises identifying an agonist of the GPCR.

6. The method of any one of claims 1 to 5, wherein the method comprises identifying a partial agonist of the GPCR.

7. The method of any one of claims 1 to 6, wherein the candidate compounds are screened as pharmaceutical agents for treating or preventing obesity or a condition related thereto.

8. The method of claim 7, wherein the condition related to obesity is selected from the group consisting of hypertension, insulin resistance, metabolic syndrome, Type 2 diabetes, dyslipidemia, atherosclerosis, coronary heart disease and stroke.

9. The method of any one of claims 1 to 6, wherein the candidate compounds are screened as pharmaceutical agents for promoting satiety.

10. The method of any one of claims 1 to 6, wherein the candidate compounds are screened as pharmaceutical agents for treating or preventing hyperphagia.

11. The method of any one of claims 1 to 6, wherein the candidate compounds are screened as pharmaceutical agents for treating or preventing pyrexia.

12. The method of any one of claims 1 to 6, wherein the candidate compounds are screened as pharmaceutical agents for treating or preventing an inflammation-associated disorder.

13. The method of any one of claims 1 to 4, wherein the method comprises identifying an inverse agonist of the GPCR.

14. The method of any one of claims 1 to 4, wherein the method comprises identifying an antagonist of the GPCR.

15. The method of any one of claims 1 to 4, 13 and 14, wherein the candidate compounds are screened as pharmaceutical agents for treating or preventing a cachexia.

16. The method of claim 15, wherein the cachexia is selected from the group consisting of AJDS-related weight loss, cancer-related weight loss and anorexia-related weight loss.

17. The method of any one of claims 1 to 6, 13 and 14, wherein the candidate compounds are screened as pharmaceutical agents for modulating an energy homeostasis-related parameter selected from the group consisting of body mass, adiposity, percentage body fat and food intake.

18. The method according to any one of claims 5 to 12 and 17, wherein the method further comprises formulating said agonist or partial agonist as a pharmaceutical.

19. The method according to any one of claims 13 to 17, wherein the method further comprises forumulating said inverse agonist or antagonist as a pharmaceutical.

20. The method of any one of claims 1 to 19, wherein said determining is through the measurement of the level of a second messenger.

21. The method of claim 20, wherein the second messenger is cAMP.

22. The method of any one of claims 1 to 19, wherein said determining is by a process comprising the use of a Melanophore assay or by a process comprising the measurement of GTP'vS binding to a membrane comprising the GPCR or by a process comprising the use of a cAMP-responsive reporter assay.

23. A modulator identifiable according to the method of any one of claims 1 to 22.

24. A pharmaceutical composition comprising a modulator of a vertebrate GPRl 01 receptor and a pharmaceutically acceptable carrier.

25. A method of preparing a pharmaceutical composition comprising admixing a modulator of a vertebrate GPRlOl receptor and a pharmaceutically acceptable carrier.

26. A method of increasing hypothalamic proopiomelanocortin (POMC)-derived biologically active peptide secretion comprising administering to a vertebrate in need thereof a therapeutically effective amount of an agonist or a partial agonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the agonist or the partial agonist and a pharmaceutically acceptable carrier.

27. A method of treating or preventing obesity or a condition related thereto comprising administering to a vertebrate in need thereof a therapeutically effective amount of an agonist or a partial agonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the agonist or the partial agonist and a pharmaceutically acceptable carrier.

28. The method of claim 27, wherein the condition related to obesity is selected from the group consisting of hypertension, insulin resistance, metabolic syndrome, Type 2 diabetes, dyslipidemia, atherosclerosis, coronary heart disease, and stroke.

29. A method of promoting satiety in a vertebrate comprising administering to a vertebrate in need thereof a therapeutically effective amount of an agonist or a partial agonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the agonist or the partial agonist and a pharmaceutically acceptable carrier.

30. A method of treating or preventing hyperphagia comprising administering to a vertebrate in need thereof a therapeutically effective amount of an agonist or a partial agonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the agonist or the partial agonist and a pharmaceutically acceptable carrier.

31. A method of treating or preventing pyrexia comprising administering to a vertebrate in need thereof a therapeutically effective amount of an agonist or a partial agonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the agonist or the partial agonist and a pharmaceutically acceptable carrier.

32. A method of treating or preventing an inflammation-associated disorder comprising administering to a vertebrate in need thereof a therapeutically effective amount of an agonist or a partial agonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the agonist or the partial agonist and a pharmaceutically acceptable carrier.

33. A method of decreasing body mass, of decreasing adiposity, of decreasing percentage body fat, or of decreasing food intake comprising administering to a vertebrate in need thereof a therapeutically effective amount of an agonist or a partial agonist of the vertebrate GPRl 01 receptor or of a pharmaceutical composition comprising the agonist or the partial agonist and a pharmaceutically acceptable carrier.

34. The method of any one of claims 26 to 33 wherein the vertebrate is a mammal or a human.

35. A method of decreasing hypothalamic proopiomelanocortin (POMC)-derived biologically active peptide secretion comprising administering to a vertebrate in need thereof a therapeutically effective amount of an inverse agonist or an antagonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the inverse agonist or the antagonist and a pharmaceutically acceptable carrier.

36. A method of treating or preventing a cachexia comprising administering to a vertebrate in need thereof a therapeutically effective amount of an inverse agonist or an antagonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the inverse agonist or the antagonist and a pharmaceutically acceptable carrier.

37. The method of claim 36, wherein the cachexia is selected from the group consisting of AEDS-related weight loss, cancer-related weight loss and anorexia-related weight loss.

38. A method of increasing body mass, of increasing adiposity, of increasing percentage body fat, or of increasing food intake comprising administering to a vertebrate in need thereof a therapeutically effective amount of an inverse agonist or an antagonist of the vertebrate GPRlOl receptor or of a pharmaceutical composition comprising the inverse agonist or the antagonist and a pharmaceutically acceptable carrier.

39. The method of any one of claims 35 to 38 wherein the vertebrate is a mammal or a human.

40. Use of an agonist or a partial agonist of a vertebrate GPRlOl receptor in the manufacture of a medicament for increasing hypothalamic proopiomelanocortin (POMC)-derived biologically active peptide secretion.

41. Use of an agonist or a partial agonist of a vertebrate GPR 101 receptor in the manufacture of a medicament for treating or preventing obesity or a condition related thereto.

42. The use of claim 41, wherein the condition related to obesity is selected from the group consisting of hypertension, insulin resistance, metabolic syndrome, Type 2 diabetes, dyslipidemia, atherosclerosis, coronary heart disease, and stroke.

43. Use of an agonist or a partial agonist of a vertebrate GPRlOl receptor in the manufacture of a medicament for promoting satiety.

44. Use of an agonist or a partial agonist of a vertebrate GPRl 01 receptor in the manufacture of a medicament for the treatment or prevention of hyperphagia.

45. Use of an agonist or a partial agonist of a vertebrate GPRl 01 receptor in the manufacture of a medicament for the treatment or prevention of pyrexia.

46. Use of an agonist or a partial agonist of a vertebrate GPRlOl receptor in the manufacture of a medicament for treating or preventing an inflammation-associated disorder.

47. Use of an agonist or a partial agonist of a vertebrate GPRlOl receptor in the manufacture of a medicament for decreasing body mass, for decreasing adiposity, for decreasing percentage body fat, or for decreasing food intake.

48. Use of an inverse agonist or an antagonist of a vertebrate GPRl 01 receptor in the manufacture of a medicament for decreasing hypothalamic proopiomelanocortin (POMC)-derived biologically active peptide secretion.

49. Use of an inverse agonist or an antagonist of a vertebrate GPRl 01 receptor in the manufacture of a medicament for treating or preventing a cachexia in the vertebrate.

50. The use of claim 49, wherein the cachexia is selected from the group consisting of AIDS-related weight loss, cancer-related weight loss and anorexia-related weight loss.

51. Use of an inverse agonist or an antagonist of a vertebrate GPRlOl receptor in the manufacture of a medicament for increasing body mass, for increasing adiposity, for increasing percentage body fat, or for increasing food intake.

52. A method of screening candidate compounds as pharmaceutical agents for a POMC-derived biologically active peptide-related disorder, said method comprising:
(a) contacting a candidate compound with a recombinant host cell or
membrane thereof that comprises a GPCR, under conditions which permit interaction between said receptor and said candidate compound, wherein
said receptor comprises an amino acid sequence selected from the group
consisting of:
(i) the amino acid sequence of SEQ ID NO: 2;

(ii) the amino acid sequence of a G protein-coupled receptor encoded
by a polynucleotide that is amplifiable by polymerase chain reaction
(PCR) on a human DNA sample using specific primers SEQ ID
NO: 7 and SEQ ID NO: 8;
(iii) the amino acid sequence of SEQ ID NO: 4;
(iv) the amino acid sequence of SEQ ID NO:6;
(v) the amino acid sequence of a G protein-coupled receptor encoded
by a polynucleotide hybridizing under stringent conditions to the
complement of SEQ ID NO: 1 , SEQ TD NO: 3 or SEQ ID NO: 5;
(vi) the amino acid sequence of a G protein-coupled receptor that has an
amino acid sequence having at least about 70% identity to SEQ ID
NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6;
(vii) the amino acid sequence of a G protein-coupled receptor having a
variant of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO:
■ 4 or SEQ ID NO: 6; and
(viii) a biologically active fragment of any one of (i) to (vii); and
(b) detecting a ligand bound to said GPCR.

53. The method of claim 52, wherein the GPCR comprises SEQ ID NO: 2 or the amino acid sequence of a G protein-coupled receptor that has an amino acid sequence having at

' least about 70% identity to SEQ ID NO: 2.

54. The method of claim 52 or claim 53, wherein the POMC-derived biologically active peptide is selected from the group consisting of ACTH, /3-endorphin, oMSH, β- MSH and γ-MSH.

55. The method of any one of claims 52 to 54, wherein the screen is for radioimaging agents for identifying a vertebrate at risk for or progressing toward obesity or a condition related thereto.

56. Use of a GPCR to screen candidate compounds as modulators of hypothalamic proopiomelanocortin (POMC)-derived biologically active peptide secretion or as pharmaceutical agents for a POMC-derived biologically active peptide-related disorder, wherein the GPCR comprises an amino acid sequence selected from the group consisting of:
(a) the amino acid sequence of SEQ ID NO: 2;
(b) the amino acid sequence of a G protein-coupled receptor encoded by a
polynucleotide that is ampliflable by polymerase chain reaction (PCR) on a human DNA sample using specific primers SEQ ID NO: 7 and SEQ ID
NO: 8;
(c) the amino acid sequence of SEQ ID NO: 4;
(d) the amino acid sequence of SEQ ID NO:6;
(e) the amino acid sequence of a G protein-coupled receptor encoded by a
polynucleotide hybridizing under stringent conditions to the complement of SEQ ID NO: 1, SEQ ID NO: 3 or SEQ ID NO: 5;
(f) the amino acid sequence of a G protein-coupled receptor that has an amino acid sequence having at least about 70% identity to SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO: 6;
(g) the amino acid sequence of a G protein-coupled receptor having a variant of the amino acid sequence of SEQ ID NO: 2, SEQ ID NO: 4 or SEQ ID NO:
6; and
(h) a biologically active fragment of any one of (a) to (g).

57. The use of claim 56, wherein the GPCR comprises the amino acid sequence of SEQ ID NO: 2 or the amino acid sequence of a G protein-coupled receptor that has an amino acid sequence having at least about 70% identity to SEQ ID NO: 2.

58. The use of claim 56 or claim 57, wherein the POMC-derived biologically active peptide is selected from the group consisting of ACTH5 j8-endorphin, α-MSH, /3-MSH and γ-MSH.

59. The use of any one of claims 56 to 58, wherein the screen is for an agonist of the GPCR.

60. The use of any one of claims 56 to 59, wherein the screen is for a partial agonist of the GPCR.

61. The use of any one of claims 56 to 58, wherein the screen is for an inverse agonist of the GPCR.

62. The use of any one of claims 56 to 58, wherein the screen is for an antagonist of the GPCR.