US EPA

7457980 

Journal Article 

Characterization of tunable piperidine and piperazine carbamates as inhibitors of endocannabinoid hydrolases 

Long, JZ; Jin, X; Adibekian, A; Li, W; Cravatt, BF 

2010 

Yes 

Journal of Medicinal Chemistry
ISSN: 0022-2623
EISSN: 1520-4804 

53 

4 

1830-1842 

English 

10.1021/jm9016976 

Monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH) are two enzymes from the serine hydrolase superfamily that degrade the endocannabinoids 2-arachidonoylglycerol and, anandamide, respectively. We have recently discovered that, MAGL and, FAAH are both inhibited by carbamates bearing an N-piperidine/piperazine group. Piperidine/piperazine carbamates show excellent in vivo activity, raising brain endocannabinoid levels and producing CB1-dependent behavioral effects in mice, suggesting that they represent a promising class of inhibitors for studying the endogenous functions of MAGL and FAAH. Herein, we disclose a full account of the syntheses, structure-activity relationships, and, inhibitory activities of piperidine/piperazine carbamates against members of the serine hydrolase family. These scaffolds can be tuned for MAGL-selective or dual MAGL-FAAH inhibition by the attachment of an, appropriately substituted bisarylcarbinol or aryloxybenzyl moiety, respectively, on the piperidine/piperazine ring. Modifications to the piperidine/piperazine ring ablated inhibitory activity, suggesting a strict requirement for a six-membered ring to maintain potency. © 2010 American Chemical Society. 

1 benzyl 4 (hydroxybis(4 methoxyphenyl)methyl)pyrrolidin 2 one; 4 (diphenylmethylene)piperadine; 4 nitrophenyl 2,2 diphenyl 1 oxa 6 azaspirol[2.5]octane 6 carboxylate; 4 nitrophenyl 3 (hydroxybis(4 methoxyphenyl)methyl)pyrrolidine 1 carboxylate; 4 nitrophenyl 3,3 diphenylpropyl(ethyl)carbamate; 4 nitrophenyl 4 (4 benzyloxy) 2 methoxybenzyl)piperazine 1 carboxylate; 4 nitrophenyl 4 (4 methoxybenzyl)piperazine 1 carboxylate; 4 nitrophenyl 4 (biphenyl 2 ylmethyl)piperazine 1 carboxylate; 4 nitrophenyl 4 (bis(3,4 dimethoxyphenyl)(hydroxy)methyl)piperidine 1 carboxylate; 4 nitrophenyl 4 (bis(4 chlorophenyl)(hydroxy)methyl)piperidine 1 carboxylate; 4 nitrophenyl 4 (bis(4 dimethylamino)phenyl)hydroxy)methyl)piperidine 1 carboxylate; 4 nitrophenyl 4 (diphenylmethylene)piperadine 1 carboxylate; 4 nitrophenyl 4 (hydroxybis(2 methoxyphenyl)methyl)piperidine 1 carboxylate; 4 nitrophenyl 4 (hydroxybis(3 methoxyphenyl)methyl)piperidine 1 carboxylate; 4 nitrophenyl 4 (hydroxydinaphthalen 2 ylmethyl)piperidine 1 carboxylate; 4 nitrophenyl 4 (hydroxydiphenylmethyl)piperadine 1 carboxylate; 4 nitrophenyl 4 (naphthalen 2 ylmethyl)piperazine 1 carboxylate; 4 nitrophenyl 4 (quinolin 2 ylmethyl)piperazine 1 carboxylate; 4 nitrophenyl 4 benzylpiperazine 1 carboxylate; 4 nitrophenyl 4 biphenyl 4 ylmethyl)piperzine 1 carboxylate; carbamic acid derivative; endocannabinoid; hydrolase inhibitor; piperazine; piperidine; serine; tert butyl 4 (4 methoxybenzyl)piperazine 1 carboxylate; tert butyl 4 hydroxybis(4 methoxyphenyl)methyl)piperadine 1 carboxylate; tert butyl 4 naphthalen 2 ylmethyl)piperazine 1 carboxylate; unclassified drug; unindexed drug; animal experiment; animal tissue; article; controlled study; drug inhibition; drug synthesis; IC 50; in vivo study; mouse; nonhuman; polyacrylamide gel electrophoresis; protein function; structure activity relation; Amidohydrolases; Animals; Brain; Carbamates; Mice; Monoacylglycerol Lipases; Piperazines; Piperidines; Structure-Activity Relationship