Novel methods for identifying improved, non-sedating alpha-2 agonists

• US 20050059664A1
• Filed: 07/15/2004
• Published: 03/17/2005
• Est. Priority Date: 09/12/2003
• Status: Abandoned Application

• Current Assignee: Allergan Incorporated (Abbvie Incorporated)
• Original Assignee: Allergan Incorporated (Abbvie Incorporated)
• Inventors: Donello, John E., Gil, Daniel W.
• Application Number:
  US10/891,740
• Publication Number:
  US 20050059664A1
• Time in Patent Office: Days
• US Class Current: 514/249
• CPC Class Codes: A61K 31/4164 1,3-Diazoles
• CPC Class Codes: A61K 31/498 Pyrazines or piperazines ortho- and peri-condensed with carbocyclic ring systems, e.g. quinoxaline, phenazine
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 15/08 for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 21/02 Muscle relaxants, e.g. for tetanus or cramps
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/06 Antimigraine agents
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 25/36 Opioid-abuse
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 27/06 : Antiglaucoma agents or miotics
• CPC Class Codes: A61P 29/00 : Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/04 : Anorexiants; Antiobesity agents
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 31/22 : for herpes viruses
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 41/00 : Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/50 : for increasing or potentiating the activity of insulin
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/06 : Antiarrhythmics
• CPC Class Codes: A61P 9/08 : Vasodilators for multiple indications
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Abstract

The present invention provides methods of preventing or alleviating sympathetically-enhanced conditions, neurological conditions, ocular conditions and chronic pain without concomitant sedation by peripherally administering to a subject an effective amount of an α-2A/α-1A selective agonist, thereby preventing or alleviating the condition or chronic pain without concomitant sedation, where the selective agonist has an α-1A efficacy less than that of brimonidine or a ratio of α-1A/α-2A potency greater than that of brimonidine.

Claims

1. A method of preventing or alleviating a sympathetically-enhanced condition without concomitant sedation, comprising peripherally administering to a subject an effective amount of an α

-2A/α

-1A selective agonist, thereby preventing or alleviating said sympathetically enhanced condition without concomitant sedation,

wherein said selective agonist has an α

-1A efficacy less than that of brimonidine or a ratio of α

-1A/α

-2A potency greater than that of brimonidine.

2. The method of claim 1, wherein said selective agonist has an α

-1A efficacy less than that of brimonidine.

3. The method of claim 1, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least 30% greater than that of brimonidine.

4. The method of claim 1, wherein said effective agent has an α

-1A/α

-2A EC₅₀ ratio which is at least two-fold greater than that of brimonidine.

5. The method of claim 1, wherein said effective agent has an α

-1A/α

-2A EC₅₀ ratio which is at least ten-fold greater than that of brimonidine.

6. The method of claim 1, wherein said condition is sensory hypersensitivity.

7. The method of claim 6, wherein said condition is sensory hypersensitivity associated with headache.

8. The method of claim 7, wherein said condition is sensory hypersensitivity associated with migraine.

9. The method of claim 1, wherein said condition is gastrointestinal disease.

10. The method of claim 9, wherein said gastrointestinal disease is irritable bowel syndrome.

11. The method of claim 9, wherein said gastrointestinal disease is dyspepsia.

12. The method of claim 1, wherein said condition is a dermatological condition.

13. The method of claim 12, wherein said dermatological condition is psoriasis.

14. The method of claim 1, wherein said condition is a cardiovascular disorder.

15. The method of claim 14, wherein said condition is tachycardia.

16. The method of claim 1, wherein said condition is a disorder of peripheral vasoconstriction.

17. The method of claim 1, wherein said condition is panic attack.

18. The method of claim 1, wherein said condition is a metabolic disorder.

19. The method of claim 18, wherein said metabolic disorder is type II diabetes.

20. The method of claim 18, wherein said metabolic disorder is insulin-resistance.

21. The method of claim 18, wherein said metabolic disorder is obesity.

22. The method of claim 1, wherein said condition is a disorder of muscle contraction.

23. The method of claim 22, wherein said disorder of muscle contraction is a disorder of skeletal muscle contraction.

24. The method of claim 22, wherein said disorder of muscle contraction is a disorder of smooth muscle contraction.

25. The method of claim 22, wherein said disorder of muscle contraction is spasticity.

26. The method of claim 22, wherein said disorder of muscle contraction is associated with tension type headache.

27. The method of claim 1, wherein said condition is a behavioral disorder.

28. The method of claim 1, wherein said effective amount is administered orally.

29. The method of claim 1, wherein said effective amount is administered topically.

30. The method of claim 1, wherein said effective amount is administered via a patch.

31. A method of preventing or alleviating chronic pain without concomitant sedation by peripherally administering to a subject an effective amount of an α

-2A/α

-1A selective agonist, thereby preventing or alleviating said chronic pain without concomitant sedation,

wherein said selective agonist has an α

-1A efficacy less than that of brimonidine or a ratio of α

-1A/α

-2A potency greater than that of brimonidine.

32. The method of claim 31, wherein said selective agonist has an α

-1A efficacy less than that of brimonidine.

33. The method of claim 31, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least 30% greater than that of brimonidine.

34. The method of claim 31, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least two-fold greater than that of brimonidine.

35. The method of claim 31, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least ten-fold greater than that of brimonidine.

36. The method of claim 31, wherein said chronic pain is neuropathic pain.

37. The method of claim 36, wherein said neuropathic pain is associated with diabetic neuropathy.

38. The method of claim 36, wherein said neuropathic pain is associated with post-herpetic neuralgia.

39. The method of claim 31, wherein said chronic pain is associated with cancer.

40. The method of claim 31, wherein said chronic pain is post-operative pain.

43. The method of claim 31, wherein said chronic pain is associated with Complex Regional Pain Syndrome (CRPS).

44. The method of claim 31, wherein said chronic pain is visceral pain.

45. The method of claim 44, wherein said visceral pain is associated with irritable bowel syndrome.

46. The method of claim 44, wherein said visceral pain is associated with dysmennorhea.

47. The method of claim 31, wherein said chronic pain is associated with headache.

48. The method of claim 47, wherein said headache is a migraine.

49. The method of claim 47, wherein said headache is non-vascular.

50. The method of claim 47, wherein said headache is cluster headache or daily tension headache.

51. The method of claim 31, wherein said chronic pain is muscle pain.

52. The method of claim 51, wherein said muscle pain is associated with back spasm.

53. The method of claim 31, wherein said effective amount is administered orally.

54. The method of claim 31, wherein said effective amount is administered topically.

55. The method of claim 31, wherein said effective amount is administered via a patch.

41. The method of claim 41, wherein said chronic pain is allodynic pain.

42. The method of claim 41, wherein said allodynic pain is fibromyalgic pain.

56. A method of preventing or alleviating a neurological condition without concomitant sedation by peripherally administering to a subject an effective amount of an α

-2A/α

-1A selective agonist, thereby preventing or alleviating said neurological condition without concomitant sedation,

wherein said selective agonist has an α

-1A efficacy less than that of brimonidine or a ratio of α

-1A/α

-2A potency greater than that of brimonidine.

57. The method of claim 56, wherein said selective agonist has an α

-1A efficacy less than that of brimonidine.

58. The method of claim 56, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least 30% greater than that of brimonidine.

59. The method of claim 56, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least two-fold greater than that of brimonidine.

60. The method of claim 56, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least ten-fold greater than that of brimonidine.

61. The method of claim 56, wherein said neurological condition is an acute neurological condition.

62. The method of claim 61, wherein said acute neurological condition is stroke.

63. The method of claim 61, wherein said acute neurological condition is head or spinal cord trauma.

64. The method of claim 61, wherein said acute neurological condition is seizure.

65. The method of claim 56, wherein said neurological condition is a chronic neurological condition.

66. The method of claim 56, wherein said chronic neurological condition is a neurodegenerative disease.

67. The method of claim 66, wherein said neurodegenerative disease is Alzheimer'"'"'s disease.

68. The method of claim 66, wherein said neurodegenerative disease is Parkinson'"'"'s disease.

69. The method of claim 66, wherein said neurodegenerative disease is Huntington'"'"'s disease.

70. The method of claim 66, wherein said neurodegenerative disease is amyotrophic lateral sclerosis or multiple sclerosis.

71. The method of claim 66, wherein said neurodegenerative disease is HIV-associated dementia or HIV-associated neuropathy.

72. The method of claim 66, wherein said neurodegenerative disease is an ocular disease.

73. The method of claim 72, wherein said ocular disease is glaucoma.

74. The method of claim 72, wherein said ocular disease is diabetic neuropathy

75. The method of claim 72, wherein said ocular disease is age-related macular degeneration.

76. The method of claim 65, wherein said chronic neurological condition is selected from schizophrenia, drug addiction, drug withdrawal, drug dependency, depression and anxiety.

77. The method of claim 56, wherein said effective amount is administered orally.

78. The method of claim 56, wherein said effective amount is administered topically.

79. The method of claim 56, wherein said effective amount is administered via a patch.

80. A method of preventing or alleviating an ocular condition without concomitant sedation by peripherally administering to a subject an effective amount of an α

-2A/α

-1A selective agonist, thereby preventing or alleviating said ocular condition without concomitant sedation,

wherein said selective agonist has an α

-1A efficacy less than that of brimonidine or a ratio of α

-1A/α

-2A potency greater than that of brimonidine.

81. The method of claim 80, wherein said selective agonist has an α

-1A efficacy less than that of brimonidine.

82. The method of claim 80, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least 30% greater than that of brimonidine.

83. The method of claim 80, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least two-fold greater than that of brimonidine.

84. The method of claim 80, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least ten-fold greater than that of brimonidine.

85. The method of claim 80, wherein said ocular condition is glaucoma.

86. The method of claim 80, wherein said ocular condition is macular degeneration.

87. The method of claim 80, wherein said ocular condition is retinopathy.

88. The method of claim 87, wherein said retinopathy is diabetic retinopathy.

89. The method of claim 80, wherein said effective amount is administered orally.

90. The method of claim 80, wherein said effective amount is administered topically.

91. The method of claim 80, wherein said effective amount is administered via a patch.

92. A method of screening for an α

-2A/α

-1A selective agonist that prevents or alleviates sympathetically-enhanced conditions without concomitant sedation upon peripheral administration, comprising determining the functional selectivity of an agent for activating an α

-2A receptor as compared to an α

-1A receptor,

wherein an agent which is highly selective for activating an α

-2A receptor as compared to an α

-1A receptor is an α

-2A/α

-1A selective agonist that prevents or alleviates sympathetically-enhanced conditions without concomitant sedation upon peripheral administration.

93. The method of claim 92, comprising

(a) determining potency, activity or EC₅₀ of said agent at an α

-2A receptor; and

(b) determining potency, activity or EC₅₀ of said agent at an α

-1A receptor,

wherein an agent which has an α

-1A efficacy less than that of brimonidine or a ratio of α

-1A/α

-2A potency greater than that of brimonidine is an α

-2A/α

-1A selective agonist that prevents or alleviates a sympathetically-enhanced condition without concomitant sedation.

94. The method of claim 92, wherein said selective agonist has an α

-1A efficacy less than that of brimonidine.

95. The method of claim 92, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least 30% greater than that of brimonidine.

96. The method of claim 92, wherein said selective agonist has an α

-1A/α

-2A EC₅₀ ratio which is at least two-fold greater than that of brimonidine.

97. The method of claim 92, wherein said effective agent has an α

-1A/α

-2A EC₅₀ ratio which is at least ten-fold greater than that of brimonidine.

98. The method of claim 93, wherein step (a) comprises assaying for inhibition of adenylate cyclase activity.

99. The method of claim 98, wherein said assaying for inhibition of adenylate cyclase activity is in PC12 cells stably expressing α

-2A.

100. The method of claim 99, said PC12 cells stably expressing human α

-2A.

101. The method of claim 93, wherein step (b) comprises assaying for intracellular calcium.

102. The method of claim 101, wherein intracellular calcium is assayed in HEK293 cells stably expressing α

-1A.

103. The method of claim 102, said HEK293 cells stably expressing bovine α

-1A.