Treatment of inflammation using alpha 7 receptor-binding agonists
View Patent ↗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.
1. A method of treating a patient suffering from a condition mediated by a proinflammatory cytokine, the method comprising administering to the patient a therapeutically effective amount of a selective α7 nicotinic receptor cholinergic agonist,
wherein the condition is at least one selected from the group consisting of rheumatoid arthritis, neuritis, neuralgia, arthritis, arthralgia, fasciitis, gout, and synovitis.
2. The method of claim 1 , wherein the agonist decreases the amount of the proinflammatory cytokine that is released from a macrophage in the patient.
3. The method of claim 1 , wherein the cholinergic agonist is at least one selected from the group consisting of:
cocaine methiodide;
(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid 1-(2-fluorophenyl)-ethyl ester or a pharmaceutically acceptable salt thereof;
a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein in I: R is H or CH 3 , and n is 0 or 1;
a compound of formula II, or an enantiomer or pharmaceutically acceptable salt thereof:
wherein in II:
m is 1 or 2,
n is 0 or 1,
Y is CH, N or NO,
X is O or S,
W is O, H 2 or F 2 ,
A is N or C(R 2 ),
G is N or C(R 3 ),
D is N or C(R 4 ),
with the proviso that no more than one of A, G and D is N but at least one of Y, A, G and D is N or NO,
R 1 is H or C 1 -C 4 alkyl,
R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, OH, OC 1 -C 4 alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3 and —OSO 2 CF 3 , or R 2 and R 3 , R 3 and R 4 , respectively, together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two substituents independently selected from the group consisting of H, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, OH, OC 1 -C 4 alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3 and —OSO 2 CF 3 ,
R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 4 alkyl, C(O)R 7 , C(O)NHR 8 , C(O)OR 9 , and SO 2 R 10 , or R 5 and R 6 together are (CH 2 ) j Q(CH 2 ) k where Q is O, S, NR 11 , or a bond,
j is an integer ranging from 2 to 7,
k is 0, 1 or 2,
R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from the group consisting of C 1 -C 4 alkyl, aryl, and heteroaryl;
a compound of formula III, or a pharmaceutically acceptable salt thereof:
wherein in III:
R 1 , R 6 and R 7 are independently selected from the group consisting of H and C 1 -C 4 alkyl, and R 2 is selected from the group consisting of:
R 3 , R 4 and R 5 are independently selected from the group consisting of H, C 1 -C 4 alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C 1 -C 6 alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amido having 1 to 4 carbons in the acyl, cyano, and N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl and nitro; and
a compound of formula IV, or a pharmaceutically acceptable salt thereof:
wherein in IV:
X is O or S, and R is selected from the group consisting of H, OR 1 , NHC(O)R 1 , and halogen, and
R 1 is C 1 -C 4 alkyl.
4. The method of claim 1 , wherein the cholinergic agonist is a compound of formula I, or a pharmaceutically acceptable salt thereof:
wherein in I: R is H or CH 3 , and n is 0 or 1.
5. The method of claim 4 , wherein the cholinergic agonist is (−)-spiro[1-azabicyclo[2.2.2]octane-3,5′-oxazolidin-2′-one], or a pharmaceutically acceptable salt thereof:
6. The method of claim 1 , wherein the cholinergic agonist is a compound of formula II, or an enantiomer or pharmaceutically acceptable salt thereof:
wherein in II:
m is 1 or 2;
n is 0 or 1;
Y is CH, N or NO;
X is O or S;
W is O, H 2 or F 2 ;
A is N or C(R 2 );
G is N or C(R 3 );
D is N or C(R 4 );
with the proviso that no more than one of A, G and D is N but at least one of Y, A, G and D is N or NO;
R 1 is H or C 1 -C 4 alkyl;
R 2 , R 3 and R 4 are independently selected from the group consisting of H, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, OH, OC 1 -C 4 alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3 and —OSO 2 CF 3 , or R 2 and R 3 , R 3 and R 4 , respectively, together form another six membered aromatic or heteroaromatic ring sharing A and G, or G and D, respectively, containing between zero and two nitrogen atoms, and substituted with one to two substituents independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, C 2 -C 4 alkenyl, C 2 -C 4 alkynyl, aryl, heteroaryl, OH, OC 1 -C 4 alkyl, CO 2 R 1 , —CN, —NO 2 , —NR 5 R 6 , —CF 3 and —OSO 2 CF 3 ;
R 5 and R 6 are independently selected from the group consisting of H, C 1 -C 4 alkyl, C(O)R 7 , C(O)NHR 8 , C(O)OR 9 , and SO 2 R 10 , or R 5 and R 6 together are (CH 2 ) j Q(CH 2 ) k where Q is O, S, NR 11 , or a bond;
j is an integer ranging from 2 to 7;
k is 0, 1 or 2;
R 7 , R 8 , R 9 , R 10 and R 11 are independently selected from the group consisting of C 1 -C 4 alkyl, aryl, and heteroaryl.
7. The method of claim 6 , wherein the cholinergic agonist is a compound of formula II wherein m is 1; n is 0; x is oxygen; A is C(R 2 ); G is C(R 3 ); and D is C(R 4 ).
8. The method of claim 6 , wherein the cholinergic agonist is 5′-phenylspiro[1-azabicyclo[2.2.2]octane-3,2′-(3′H)-furo[2,3-b]pyridin] or a pharmaceutically acceptable salt thereof.
9. The method of claim 1 , wherein the cholinergic agonist is a compound of formula III or a pharmaceutically acceptable salt thereof:
wherein in III:
R 1 , R 6 and R 7 are independently selected from the group consisting of H and C 1 -C 4 alkyl;
R 2 is selected from a group of
R 3 , R 4 and R 5 are independently selected from the group consisting of H, C 1 -C 4 alkyl optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, C 1 -C 6 alkoxy optionally substituted with N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, carboalkoxy having 1 to 4 carbons in the alkoxy, amino, amido having 1 to 4 carbons in the acyl, cyano, and N,N-dialkylamino having 1 to 4 carbons in each of the alkyls, halo, hydroxyl and nitro.
10. The method of claim 9 , wherein the cholinergic agonist is a compound of formula III, wherein R 2 is attached to the 3-position of the tetrahydropyridine ring, and further wherein R 3 , 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.
11. The method of claim 9 , wherein the cholinergic agonist is a compound selected from the group consisting of
formula III, wherein R 3 is hydroxyl, and wherein R 1 , R 4 , and R 5 are H;
formula III, wherein R 3 is acetylamino and wherein R 1 , R 4 , and R 5 are H;
formula III, wherein R 3 is acetoxy and wherein R 1 , R 4 , and R 5 are H;
formula III, wherein R 3 is methoxy, and wherein R 1 , R 4 , and R 5 are H;
formula III, wherein R 3 is methoxy and wherein R 1 and R 4 are H, and further wherein R 3 is attached to the 2-position of the phenyl ring, and R 5 , which is attached to the 4-position of the phenyl ring, is methoxy or hydroxy.
12. The method of claim 9 , wherein the cholinergic agonist is at least one 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, trans-3-(4-methoxycinnamylidene)anabaseine, and pharmaceutically acceptable salts thereof.
13. The method of claim 12 , wherein the cholinergic agonist is 3-(4-hydroxy-2-methoxybenzylidene)anabasine or a pharmaceutically acceptable salt thereof:
14. The method of claim 12 , wherein the cholinergic agonist is 3-(2,4-dimethoxybenzylidene)anabaseine or a pharmaceutically acceptable salt thereof:
15. The method of claim 1 , wherein the cholinergic agonist is a compound of formula IV or a pharmaceutically acceptable salt thereof:
wherein in IV:
X is O or S; and R is selected from the group consisting of H, OR 1 , NHC(O)R 1 , and halogen, wherein R 1 is a C 1 -C 4 alkyl.
16. The method of claim 15 , wherein the cholinergic agonist is at least one 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, N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(3-chlorophenylsulphonyl)benzamide, and pharmaceutically acceptable salts thereof.
17. The method of claim 15 , wherein the cholinergic agonist is N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-(phenylsulfanyl)benzamide or a pharmaceutically acceptable salt thereof.
18. The method of claim 1 , wherein the cholinergic agonist is cocaine methiodide.
19. The method of claim 1 , wherein the condition is rheumatoid arthritis.
20. The method of claim 1 , wherein the condition is arthritis.