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31. (WO2012030953) 5-HT2C RECEPTOR AGONISTS IN THE TREATMENT OF DISORDERS AMELIORATED BY REDUCTION OF NOREPINEPHRINE LEVEL
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What is claimed is:

1. A method for:

a. reducing a concentration of norepinephrine in an individual; or

b. treating a disorder ameliorated by reducing a concentration of norepinephrine in an individual;

comprising administering to said individual, by said individual or by a caregiver, one or more doses of a medicament comprising a therapeutically effective amount of a 5-HT2C receptor agonist.

2. The method according to claim 1 , comprising administering to said individual a

plurality of doses of said medicament.

3. The method according to claim 2, comprising administering to said individual one or two doses of said medicament per day for:

at least one week; or

at least one month.

4. The method according to any one of claims 1 to 3, wherein said reducing, or

amelioration of said disorder occurs:

within 56 days of administering first said dose; or

within 7 days of administering first said dose.

5. The method according to any one of claims 1 to 4, wherein said reducing, or

amelioration of said disorder is not dependent upon concomitant weight-loss in said individual.

6. The method according to any one of claims 1 to 4, wherein said individual does not lose a substantial amount of weight during said reducing or amelioration of said disorder.

7. The method according to any one of claims 1 to 4, wherein said individual loses a substantial amount of weight during said reducing or amelioration of said disorder; and wherein said reducing or amelioration of said disorder is greater than the amount of reducing or amelioration expected by said individual or said caregiver solely as a result of said individual loosing said substantial amount of weight.

8. The method according to any one of claims 1 to 7, wherein said concentration is:

a urine concentration;

a blood concentration;

a plasma concentration;

a brain concentration; or

a cerebrospinal fluid concentration.

9. The method according to any one of claims 1 to 8, wherein said reducing provides reduced concentration of norepinephrine in said individual:

at least about 10% lower than baseline;

at least about 20% lower than baseline;

at least about 30% lower than baseline;

at least about 40% lower than baseline; or

at least about 50% lower than baseline.

10. A method for maintaining said reduced concentration of norepinepherine, according to claim 9, comprising administering to said individual, by said individual or by a caregiver, one or more doses of a medicament comprising a therapeutically effective amount of a 5-HT2C receptor agonist.

1 1. The method according to claim 9 to 10, wherein said reduced concentration is:

a urine concentration;

a blood concentration;

a plasma concentration;

a brain concentration; or

a cerebrospinal fluid concentration.

12. A method for manufacturing a medicament for reducing a concentration of

norepinephrine in an individual, or for treating a disorder ameliorated by reducing a concentration of norepinephrine in an individual comprising admixing a 5-HT2C receptor agonist with at least one pharmaceutically acceptable excipient; wherein said 5- HT2C receptor agonist has been administered to a mammal in whom a norepinephrine concentration has been measured.

13. A method for manufacturing a medicament for reducing a concentration of

norepinephrine in an individual, or for treating a disorder ameliorated by reducing a concentration of norepinephrine in an individual comprising:

a. measuring a norepinephrine concentration in a mammal; and

b. admixing a 5-HT2C receptor agonist with at least one pharmaceutically acceptable excipient;

wherein said 5-HT2C receptor agonist has been administered to said mammal.

14. A method for manufacturing a medicament for reducing a concentration of

norepinephrine in an individual, or for treating a disorder ameliorated by reducing a concentration of norepinephrine in an individual comprising:

a. administering a 5-HT2C receptor agonist to a mammal;

b. measuring a norepinephrine concentration in said mammal; and

c. admixing said 5-HT2C receptor agonist with at least one pharmaceutically acceptable excipient.

15. A method for manufacturing a medicament for reducing a concentration of

norepinephrine in an individual, or for treating a disorder ameliorated by reducing a concentration of norepinephrine in an individual comprising resynthesizing a 5-HT2C receptor agonist; wherein said 5-HT2C receptor agonist has been administered to a mammal in whom a norepinephrine concentration has been measured.

16. A method for manufacturing a medicament for reducing a concentration of

norepinephrine in an individual, or for treating a disorder ameliorated by reducing a concentration of norepinephrine in an individual comprising:

a. measuring a norepinephrine concentration in a mammal; and

b. resynthesizing a 5-HT2C receptor agonist;

wherein said 5-HT2C receptor agonist has been administered to said mammal.

17. A method for manufacturing a medicament for reducing a concentration of

norepinephrine in an individual, or for treating a disorder ameliorated by reducing a concentration of norepinephrine in an individual comprising:

a. administering a 5-HT2C receptor agonist to a mammal;

b. measuring a norepinephrine concentration in said mammal; and

c. resynthesizing said 5-HT2C receptor agonist.

18. The method according to any one of claims 1 to 17, wherein said disorder is selected from: hypernorepinephrinemia, cardiomyopathy, cardiac hypertrophy, cardiomyocyte hypertrophy in post-myocardial infarction remodeling, elevated heart rate, vasoconstriction, acute pulmonary vasoconstriction, hypertension, heart failure, cardiac dysfunction after stroke, cardiac arrhythmia, metabolic syndrome, abnormal lipid

metabolism, hyperthermia, Cushing syndrome, pheochromocytoma, epilepsy, obstructive sleep apnea, insomnia, glaucoma, osteoarthritis, rheumatoid arthritis, and asthma.

19. The method according to any one of claims 1 to 18, wherein said individual is a human.

20. The method according to any one of claims 1 to 18, wherein said 5-HT2C receptor

agonist has an EC50 of:

less than about 10 μΜ at the 5 -HT2C receptor;

less than about 1 μΜ at the 5 -HT2C receptor; or

less than about 100 nM at the 5 -HT2C receptor.

21. The method according to any one of claims 1 to 20, wherein said 5-HT2C receptor

agonist is a selective 5-HT2C receptor agonist.

22. The method according to claim 21, wherein the ratio of the EC50 of said selective 5- HT2C receptor agonist at the 5-HT2C receptor to the EC50 of said selective 5-HT2C receptor agonist at the 5-HT2A receptor is:

at least about 10: 1 ;

at least about 100: 1 ; or

at least about 1000: 1.

23. The method according to claim 21 or 22, wherein the ratio of the EC50 of said selective 5-HT2C receptor agonist at the 5-HT2C receptor to the EC50 of said selective 5-HT2C receptor agonist at the 5-HT2B receptor is:

at least about 10: 1 ;

at least about 100: 1 ; or

at least about 1000: 1.

24. The method according to claim 21, wherein said selective 5-HT2C receptor agonist is a partial agonist, an antagonist, an inverse agonist, or a neutral antagonist of the 5-HT2A receptor.

25. The method according to claim 21 or 24, wherein said selective 5-HT2C receptor agonist is a partial agonist, an antagonist, an inverse agonist, or a neutral antagonist of the 5- HT2B receptor.

26. The method according to any one of claims 1 to 25, wherein said 5-HT2C receptor agonist is a small molecule.

27. The method according to any one of claims 1 to 26, wherein said 5-HT2C receptor agonist is orally-bioavailable.

28. The method according to claim 27 wherein said selective 5-HT2C receptor agonist is selected from 8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof.

29. The method according to claim 27, wherein said selective 5-HT2C receptor agonist is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate.

30. A 5-HT2C receptor agonist for use by an individual or caregiver in:

a. reducing a concentration of norepinephrine in said individual; or

b. treating a disorder ameliorated by reducing a concentration of norepinephrine in said individual.

31. The 5-HT2C receptor agonist according to claim 30, wherein said reducing or

amelioration of said disorder occurs:

within 56 days of administering first said dose; or

within 7 days of administering first said dose.

32. The 5-HT2C receptor agonist according to claim 30 or 31, wherein said reducing or amelioration of said disorder is not dependent upon concomitant weight-loss in said individual.

33. The 5-HT2C receptor agonist according to claim 30 or 31, wherein said individual does not lose a substantial amount of weight during said reducing or amelioration of said disorder.

34. The 5-HT2C receptor agonist according to claim 30 or 31, said individual loses a

substantial amount of weight during said reducing or amelioration of said disorder; and wherein said reducing or amelioration of said disorder is greater than the amount of reducing or amelioration expected by said individual or said caregiver solely as a result of said individual loosing said substantial amount of weight.

35. The 5-HT2C receptor agonist according to any one of claims 30 to 34, wherein said concentration is:

a urine concentration;

a blood concentration;

a plasma concentration;

a brain concentration; or

a cerebrospinal fluid concentration.

36. The 5-HT2C receptor agonist according to any one of claims 30 to 35, wherein said reducing provides a reduced concentration of norepinephrine in said individual:

at least about 10% lower than baseline;

at least about 20% lower than baseline;

at least about 30% lower than baseline;

at least about 40% lower than baseline; or

at least about 50% lower than baseline.

37. The 5-HT2C receptor agonist according to claim 36, for use by an individual or caregiver in reducing a concentration of norepinephrine in said individual and for maintaining said reduced concentration of norepinepherine.

38. The 5-HT2C receptor agonist according to claim 37, wherein said reduced concentration is:

a urine concentration;

a blood concentration;

a plasma concentration;

a brain concentration; or

a cerebrospinal fluid concentration.

39. The 5-HT2C receptor agonist according to any one of claims 30 to 35, wherein said disorder is selected from: hypernorepinephrinemia, cardiomyopathy, cardiac hypertrophy, cardiomyocyte hypertrophy in post-myocardial infarction remodeling, elevated heart rate, vasoconstriction, acute pulmonary vasoconstriction, hypertension, heart failure, cardiac dysfunction after stroke, cardiac arrhythmia, metabolic syndrome, abnormal lipid metabolism, hyperthermia, Cushing syndrome, pheochromocytoma, epilepsy, obstructive sleep apnea, insomnia, glaucoma, osteoarthritis, rheumatoid arthritis, and asthma.

40. The 5-HT2C receptor agonist according to any one of claims 30 to 39, wherein said individual is a human.

41. The 5-HT2C receptor agonist according to any one of claims 30 to 40, having an EC50 of:

less than about 10 μΜ at the 5 -HT2C receptor;

less than about 1 μΜ at the 5 -HT2C receptor;

less than about 100 nM at the 5 -HT2C receptor.

42. The 5-HT2C receptor agonist according to any one of claims 30 to 41, wherein said 5- HT2C receptor agonist is a selective 5-HT2C receptor agonist.

43. The 5-HT2C receptor agonist according to claim 42, wherein the ratio of the EC50 of said 5-HT2C receptor agonist at the 5-HT2C receptor to the EC50 of said 5-HT2C receptor agonist at the 5-HT2A receptor is:

at least about 10: 1 ;

at least about 100: 1 ;

at least about 1000: 1.

44. The 5-HT2C receptor agonist according to claim 42 or 43, wherein the ratio of the EC50 of said 5-HT2C receptor agonist at the 5-HT2C receptor to the EC50 of said 5-HT2C receptor agonist at the 5-HT2B receptor is:

at least about 10: 1 ;

at least about 100: 1 ;

at least about 1000: 1.

45. The 5-HT2C receptor agonist according to claim 42, wherein said 5-HT2C receptor

agonist is a partial agonist, an antagonist, an inverse agonist, or a neutral antagonist of the 5-HT2A receptor.

46. The 5-HT2C receptor agonist according to claim 42 or 45, wherein said 5-HT2C receptor agonist is a partial agonist, an antagonist, an inverse agonist, or a neutral antagonist of the 5-HT2B receptor.

47. The 5-HT2C receptor agonist according to any one of claims 30 to 46, wherein said 5- HT2C receptor agonist is a small molecule.

48. The 5-HT2C receptor agonist according to any one of claims 30 to 47, wherein said 5- HT2C receptor agonist is orally-bioavailable.

49. The 5-HT2C receptor agonist according to any one of claims 30 to 48, wherein said 5- HT2C receptor agonist is selected from (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3- benzazepine, and pharmaceutically acceptable salts, solvates, and hydrates thereof.

50. The 5-HT2C receptor agonist according to any one of claims 30 to 48, wherein said 5- HT2C receptor agonist is (R)-8-chloro-1-methyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride salt hemihydrate.