Inhibition of inflammation using alpha 7 receptor-binding cholinergic agonists

• US 20040204355A1
• Filed: 12/05/2003
• Published: 10/14/2004
• Est. Priority Date: 12/06/2002
• Status: Active Grant

• Current Assignee: The Feinstein Institute for Medical Research (Northwell Health, Inc.)
• Original Assignee: North Shore-Long Island Jewish Research Institute
• Inventors: Wang, Hong, Tracey, Kevin J.
• Granted Patent: US 7,273,872 B2
• Time in Patent Office: Days
• US Class Current: 514/12
• CPC Class Codes: A61K 31/00 Medicinal preparations containing organic active ingredients
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/444 containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/02 Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/02 Nasal agents, e.g. decongestants
• CPC Class Codes: A61P 11/04 for throat disorders
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 19/06 : Antigout agents, e.g. antihyperuricemic or uricosuric agents
• CPC Class Codes: A61P 19/08 : for bone diseases, e.g. rachitism, Paget's disease
• CPC Class Codes: A61P 21/04 : for myasthenia gravis
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
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• CPC Class Codes: A61P 27/02 : Ophthalmic agents
• 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 29/02 : without antiinflammatory effect
• 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 3/10 : for hyperglycaemia, e.g. antidiabetics
• CPC Class Codes: A61P 31/00 : Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 31/10 : Antimycotics
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
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• CPC Class Codes: A61P 33/00 : Antiparasitic agents
• CPC Class Codes: A61P 33/04 : Amoebicides
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/00 : Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• 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
• CPC Class Codes: G01N 2333/525 : Tumor necrosis factor [TNF]
• CPC Class Codes: G01N 2333/54 : Interleukins [IL]
• CPC Class Codes: G01N 33/6863 : Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
• CPC Class Codes: G01N 33/9406 : Neurotransmitters
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Methods of inhibiting release of a proinflammatory cytokine from a macrophage are provided. The methods comprise treating the macrophage with a cholinergic agonist in an amount sufficient to decrease the amount of the proinflammatory cytokine that is released from the macrophage, wherein the cholinergic agonist is selective for an α7 nicotinic receptor. Methods for inhibiting an inflammatory cytokine cascade in a patient are also provided. The methods comprise treating the patient with a cholinergic agonist in an amount sufficient to inhibit the inflammatory cytokine cascade, wherein the cholinergic agonist is selective for an α7 nicotinic receptor. Methods for determining whether a compound is a cholinergic agonist reactive with an α7 nicotinic receptor are also provided. The methods comprise determining whether the compound inhibits release of a proinflammatory cytokine from a mammalian cell. Additionally, methods for determining whether a compound is a cholinergic antagonist reactive with an α7 nicotinic receptor are provided. These methods comprise determining whether the compound reduces the ability of a cholinergic agonist to inhibit the release of a proinflammatory cytokine from a mammalian cell. Oligonucleotides or mimetics capable of inhibiting attenuation of lipopolysaccharide-induced TNF release from a mammalian macrophage upon exposure of the macrophage to a cholinergic agonist are also provided. The oligonucleotides or mimetics consist essentially of a sequence greater than 5 nucleotides long that is complementary to an mRNA of an α7 receptor. Additionally, methods of inhibiting attenuation of TNF release from a mammalian macrophage upon exposure of the macrophage to a cholinergic agonist are provided. These methods comprise treating the macrophage with the above-described oligonucleotide or mimetic.

Claims

1. A method of treating a patient suffering from a condition mediated by release of a proinflammatory cytokine comprising

treating said patient with a cholinergic agonist selective for an α

7 nicotinic receptor in an amount sufficient to decrease the amount of the proinflammatory cytokine that is released from a macrophage

wherein said condition is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, epiglottitis, achalasia, cholangitis, cholecystitis, hepatitis, Whipple'"'"'s disease, asthma, allergy, anaphylactic shock, immune complex disease, organ ischemia, reperfusion injury, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, hyperpyrexia, eosinophilic granuloma, granulomatosis, sarcoidosis, septic abortion, epididymitis, vaginitis, prostatitis, urethritis, bronchitis, emphysema, rhinitis, cystic fibrosis, pneumonitis, pneumoultramicroscopic silicovolcanoconiosis, alvealitis, bronchiolitis, pharyngitis, pleurisy, sinusitis, influenza, respiratory syncytial virus infection, herpes infection, HIV infection, hepatitis B virus infection, hepatitis C virus infection, disseminated bacteremia, Dengue fever, candidiasis, malaria, filariasis, amebiasis, hydatid cysts, burns, vasulitis, angiitis, endocarditis, arteritis, atherosclerosis, thrombophlebitis, pericarditis, myocarditis, myocardial ischemia, periarteritis nodosa, rheumatic fever, coeliac disease, congestive heart failure, adult respiratory distress syndrome, chronic obstructive pulmonary disease, meningitis, encephalitis, neuritis, neuralgia, spinal cord injury, paralysis, uveitis, arthritides, arthralgias, osteomyelitis, fasciitis, Paget'"'"'s disease, gout, periodontal disease, rheumatoid arthritis, synovitis, myasthenia gravis, thryoiditis, systemic lupus erythematosus, Goodpasture'"'"'s syndrome, Behcets'"'"'s syndrome, allograft rejection, graft-versus-host disease, ankylosing spondylitis, Berger'"'"'s disease, ankylosing spondylitis, Berger'"'"'s disease, Retier'"'"'s syndrome, and Hodgkins disease.

2. The method of claim 1, wherein the proinflammatory cytokine is selected from the group consisting of tumor necrosis factor (TNF), interleukin (IL)-1β

, IL-6, IL-18 and HMG-1.

3. The method of claim 1, wherein the proinflammatory cytokine is TNF.

4. The method of claim 1, wherein the cholinergic agonist is selected from the group consisting of a quaternary analog of cocaine;

(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester;

a compound of formula I;

5. The method of claim 1, wherein the cholinergic agonist is a compound of formula I:

6. The method of claim 5, wherein the cholinergic agonist is (−

)-spiro[1-azabicyclo[2.2.2]octane-3,5′

-oxazolidin-2′

-one]

7. The method of claim 1, wherein the cholinergic agonist is a compound of formula II:

8. The method of claim 7, wherein the cholinergic agonist is a compound of formula II wherein m is 1;

n is 0;

p is 0;

x is oxygen;

A is C(R²);

G is C(R³); and

D is C(R⁴).

9. The method of claim 7, wherein the cholinergic agonist is 5′

-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′

-(3′

H)-furo[2,3-b]pyridin].

10. The method of claim 1, wherein the cholinergic agonist is a compound of formula III:

11. The method of claim 10, wherein the cholinergic agonist is a compound of formula III, wherein R₂ is attached to the 3-position of the tetrahydropyridine ring, and further wherein R₃, which is attached to the 4- or the 2- position of the phenyl ring, is selected from the group consisting of amino, hydroxyl, chloro, cyano, dimethylamino, methyl, methoxy, acetylamino, acetoxy, and nitro.

12. The method of claim 10, wherein the cholinergic agonist is a compound selected from the group consisting of formula III, wherein R₃ is hydroxyl, and wherein R₁, R₄, and R₅ are hydrogen;

formula III, wherein R₃ is acetylamino and wherein R₁, R₄, and R₅ are hydrogen;

formula III, wherein R₃ is acetoxy and wherein R₁, R₄, and R₅ are hydrogen;

formula III, wherein R₃ is methoxy, and wherein R₁, R₄, and R₅ are hydrogen;

formula III, wherein R₃ is methoxy and wherein R₁ and R₄ are hydrogen, and further wherein R₃ is attached to the 2-position of the phenyl ring, and R₅, which is attached to the 4-position of the phenyl ring, is methoxy or hydroxy.

13. The method of claim 10, wherein the cholinergic agonist is is selected from the group consisting of 3-2,4-dimethoxybenzylidine anabaseine (DMXB-A), 3-(4-hydroxybenzylidene)anabaseine, 3-(4-methoxybenzylidene)anabaseine, 3-(4-aminobenzylidene)anabaseine, 3-(4-hydroxy-2-methoxybenzylidene)anabaseine, 3-(4-methoxy-2-hydroxybenzylidene)anabaseine, trans-3-cinnamylidene anabaseine, trans-3-(2-methoxy-cinnamylidene)anabaseine and trans-3-(4-methoxy-cinnamylidene)anabaseine.

14. The method of claim 10, wherein the cholinergic agonist is 3-(4-hydroxy-2-methoxybenzylidene)anabasine

15. The method of claim 10, wherein the cholinergic agonist is 3-(2,4-dimethoxybenzylidene)anabaseine.

16. The method of claim 1, wherein the cholinergic agonist is a compound of formula IV:

17. The method of claim 15, wherein the cholinergic agonist is selected from a group consisting of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-hydroxyphenoxy)benzamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(4-acetamidophenoxy)benzamide, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide, and N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulphonyl)benzamide.

18. The method of claim 15, wherein the cholinergic agonist is N-[(3R)-1-azabicyclo[2.2.2]oct-3 -yl]-4-(phenylsulfanyl)benzamide.

19. The method of claim 1, wherein the cholinergic agonist is cocaine methiodide.

20. The method of claim 1 wherein the condition is selected from the group consisting of appendicitis, peptic, gastric and duodenal ulcers, peritonitis, pancreatitis, hepatitis, asthma, allergy, anaphylactic shock, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, septic abortion, disseminated bacteremia, bums, coeliac disease, congestive heart failure, adult respiratory distress syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosis, myocardial ischemia, spinal cord injury, paralysis, allograft rejection and graft-versus-host disease.

21. The method of claim 1 wherein the condition selected from the group consisting of appendicitis, peptic, gastric or duodenal ulcers, peritonitis, pancreatitis, hepatitis, asthma, allergy, anaphylactic shock, organ necrosis, hay fever, sepsis, septicemia, endotoxic shock, cachexia, septic abortion, disseminated bacteremia, bums, congestive heart failure, adult respiratory distress syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosis, myocardial ischemia, cerebral infarction, cerebral embolism, spinal cord injury, paralysis, allograft rejection or graft-versus-host disease.

22. The method of claim 1 wherein the condition is selected from the group consisting of peritonitis, pancreatitis, sepsis, endotoxic shock, adult respiratory distress syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosis, myocardial ischemia, allograft rejection, asthma, graft-versus-host-disease, congestive heart failure and cystic fibrosis.

23. The method of claim 1, wherein the condition selected from the group consisting of peritonitis, pancreatitis, sepsis, endotoxic shock, cachexia, adult respiratory distress syndrome, chronic obstructive pulmonary disease, rheumatoid arthritis, systemic lupus erythematosis, myocardial ischemia, and allograft rejection.

24. The method of claim 1, wherein the condition is sepsis.

25. A method for determining whether a compound is a cholinergic agonist selective for an α

7 nicotinic receptor, the method comprising

determining whether the compound inhibits release of a proinflammatory cytokine from a mammalian cell, and

determining whether the compound is a cholinergic agonist reactive with at least one nicotinic receptor that is not α

7,

wherein a compound that inhibits the release of the proinflammatory cytokine from the mammalian cell, but is not a cholinergic agonist reactive with at least one nicotinic receptor that is not α

7, is a cholinergic agonist selective for an α

7 nicotinic receptor.

26. The method of claim 25, wherein the proinflammatory cytokine is selected from the group consisting of tumor necrosis factor (TNF), interleukin (IL)-1β

, IL-6, IL-18 and HMG-1.

27. The method of claim 25 wherein the proinflammatory cytokine is TNF.

28. The method of claim 25 wherein the mammalian cell is an immune cell.

29. The method of claim 25 wherein the mammalian cell is a macrophage.

30. The method of claim 25 further comprising treating the mammalian cell with an agent that stimulates a proinflammatory cytokine cascade.

31. The method of claim 30, wherein the agent is LPS.

32. The method of claim 25 wherein the determination of inhibition of proinflammatory cytokine release comprises measurement of mRNA of the proinflammatory cytokine.

33. The method of claim 25 wherein the determination of inhibition of proinflammatory cytokine release comprises measurement of the proinflammatory cytokine protein.

34. The method of claim 25 wherein the determination of inhibition of proinflammatory cytokine release comprises measurement of proinflammatory cytokine activity.

35. A method for determining whether a compound is a cholinergic antagonist reactive with an α

7 nicotinic receptor, the method comprising determining whether the compound reduces the ability of a cholinergic agonist to inhibit the release of a proinflammatory cytokine from a mammalian cell,

wherein a compound that reduces the ability of a cholinergic agonist to inhibit the release of a proinflammatory cytokine from a mammalian cell is a cholinergic antagonist reactive with an α

7 receptor.

36. The method of claim 35, wherein the proinflammatory cytokine is selected from the group consisting of tumor necrosis factor (TNF), interleukin (IL)-1β

, IL-6, IL-18 and HMG-1.

37. The method of claim 35, wherein the proinflammatory cytokine is TNF.

38. The method of claim 35, wherein the mammalian cell is an immune cell.

39. The method of claim 35, wherein the mammalian cell is a macrophage.

40. The method of claim 35, further comprising treating the mammalian cell with an agent that stimulates a proinflammatory cytokine cascade.

41. The method of claim 40, wherein the agent is LPS.

42. The method of claim 35, wherein the determination of whether the compound reduces the ability of the cholinergic agonist to inhibit the release of a proinflammatory cytokine from a mammalian cell comprises measurement of mRNA of the proinflammatory cytokine.

43. The method of claim 35, wherein the determination of whether the compound restrains the ability of the cholinergic agonist to inhibit the release of a proinflammatory cytokine from a mammalian cell comprises measurement of the proinflammatory cytokine protein.

44. The method of claim 35, wherein the determination of whether the compound restrains the ability of the cholinergic agonist to inhibit the release of a proinflammatory cytokine from a mammalian cell comprises measurement of proinflammatory cytokine activity.

45. A method for determining whether a test compound has the ability to inhibit inflammation, the method comprising determining whether the test compound is a cholinergic agonist reactive with an α

7 nicotinic receptor.

46. The method of claim 45, wherein the receptor is on a macrophage.

47. A method for determining whether a test compound has the ability to inhibit inflammation, the method comprising determining whether the test compound inhibits binding of an antagonist to an α

7 nicotinic receptor.

48. The method of claim 47, wherein the antagonist to an α

7 receptor is bungarotoxin.

49. An oligonucleotide or mimetic capable of inhibiting attenuation of lipopolysaccharide-induced TNF release from a mammalian macrophage upon exposure of the macrophage to a cholinergic agonist, wherein the oligonucleotide or mimetic consists essentially of a sequence greater than 5 nucleotides long that is complementary to an mRNA of an α

7 receptor.

50. The oligonucleotide or mimetic of claim 49, wherein the sequence is complementary to a transcription initiation region of the mRNA.

51. The oligonucleotide of claim 49, wherein the sequence comprises 5′

-gcagcgcatgttgagtcccg-3′

(SEQ ID NO;

     19).

52. The oligonucleotide or mimetic of claim 49, wherein the sequence consists essentially of 5′

-gcagcgcatgttgagtcccg-3′

(SEQ ID NO;

     19).

53. A method of inhibiting attenuation of TNF release from a mammalian macrophage upon exposure of the macrophage to a cholinergic agonist, the method comprising treating the macrophage with the oligonucleotide or mimetic of claim 49.

54. The method of claim 53, wherein the macrophage is in a mammal.

55. The method of claim 54, wherein the mammal is a human.