Allosteric modulators of the cannabinoid 1 receptor
The present technology relates to compounds and compositions of Formulas I, II, VII, and VIII, and methods using such compounds. The compounds and compositions described herein may be used in the treatment or prophylaxis of addiction, metabolic syndrome, obesity, and/or a CB1 receptor-mediated disorder.
1. A compound according to formula VIII
stereoisomers thereof, tautomers thereof, solvates thereof, or pharmaceutically acceptable salts thereof;
wherein
v and vi designate the particular bonds indicated in formula VIII;
R 49 is selected from formulas J or M:
where X 7 , X 8 , and X 9 are each independently O, N, or S;
R 54 , R 55 , and R 56 are each independently H, cyano, amino, or a substituted or unsubstituted alkyl, alkanoyl, alkanoyloxy, or aryl group when X 7 , X 8 , or X 9 are respectively N and are absent when X 7 , X 8 , or X 9 are respectively O or S;
R 50 is a substituted or unsubstituted aryl or heteroaryl group;
R 51 and R 52 are each independently H or a substituted or unsubstituted alkyl group, or R 51 and R 52 together form a 3- or 4-membered cycloalkyl ring;
R 53 is a substituted aryl group where one and only one of the substituents is;
where one of R 57 or R 58 is
and the other is H, azido, trifluoromethyldiazirido, isocyano, isothiocyano, pentafluorosulfanyl, or a substituted or unsubstituted alkyl, alkanoyl, alkanoyloxy, aryloyl, or aryloyloxy group;
R 59 and R 60 are each independently H, halo, azido, trifluoromethyldiazirido, isocyano, isothiocyano, pentafluorosulfuryl, or a substituted or unsubstituted alkyl, alkanoyl, alkanoyloxy, aryloyl, or aryloyloxy group;
Y 9 is CH;
Y 10 and Y 11 are each independently C or N, provided that when Y 10 or Y 11 is N then R 41 or R 42 respectively is absent;
Y 12 is CH, N, O, S, S(O), or S(O) 2 ;
R 61 , R 62 , and R 63 are each independently H, azido, trifluoromethyldiazirido, isocyano, isothiocyano, or a substituted or unsubstituted alkyl group;
R 64 is H or a substituted or unsubstituted alkyl group when Y 12 is CH or N and is absent when Y 12 is O, S, S(O), or S(O) 2 ;
t is 0 or 1; and
s is 0 or 1
wherein the compound is a modulator of a cannabinoid 1 (CB1) receptor.
2. A composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
3. A pharmaceutical composition for treating a condition, the pharmaceutical composition comprising a therapeutically effective amount of the compound of claim 1 , wherein the condition is addiction, metabolic syndrome, or obesity.
4. A method comprising administering a therapeutically effective amount of a compound of claim 1 , or administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of claim 1 , to a subject suffering from addiction, metabolic syndrome, or obesity.
5. A method comprising inhibiting β-arrestin in a subject by administering a therapeutically effective amount of a compound of claim 1 .
6. The method of claim 5 , wherein the subject is suffering from addiction, a metabolic disorder, obesity, or cancer.
7. The method of claim 5 , comprising inhibiting β-arrestin recruitment at least 10 times more than inhibiting cyclic AMP formation by administering the therapeutically effective amount of the compound.
8. The method of claim 7 , wherein the subject is suffering from addiction, a metabolic disorder, obesity, or cancer.
9. A method for treating an addiction in a subject comprising administering a therapeutically effective amount of a compound of claim 1 .
10. The method of claim 9 , wherein the addiction is to at least one of nicotine, ethanol, cocaine, opioids, amphetamines, marijuana, and synthetic cannabinoid agonists.
11. The compound of claim 1 which is
12. The compound of claim 1 which is