The synthesis and biological evaluation of para-substituted phenolic N-alkyl carbamates as endocannabinoid hydrolyzing enzyme inhibitors.
A series of para-substituted phenolic N-alkyl carbamates were evaluated for their FAAH and MGL inhibitory activities. The compounds were generally selective for FAAH, with IC(50) values in the nM range, whereas inhibition of MGL required concentrations three orders of magnitude higher. The most potent compounds, dodecylcarbamic acid 4-(4,5-dihydrothiazol-2-yl)phenyl (12) and 4-(1,2,3-thiadiazol-4-yl)phenyl (26) esters, inhibited FAAH and MGL with IC(50) values at the low-nanomolar (IC(50)s; 0.0063 and 0.012 microM) and the low-micromolar ranges (IC(50)s; 2.1 and 1.0 microM), respectively. Compound 26 also inhibited both FAAH-dependent AEA uptake and AEA hydrolysis (IC(50); 0.082 microM) by intact RBL2H3 cells, and could also reduce 2-AG hydrolysis by these cells at concentrations >or=0.030 microM.
Minkkilä
Anna
A
University of Kuopio, Department of Pharmaceutical Chemistry, Kuopio, Finland. anna.minkkila@uku.fi
Myllymäki
Mikko J
MJ
Saario
Susanna M
SM
Castillo-Melendez
Joel A
JA
Koskinen
Ari M P
AM
Fowler
Christopher J
CJ
Leppänen
Jukka
J
Nevalainen
Tapio
T
D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002219:Carbamates / Q000737:chemistry*; D045744:Cell Line, Tumor; D004583:Electrons; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D006868:Hydrolysis / Q000187:drug effects; D008297:Male; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D010636:Phenols / Q000737:chemistry*; D051381:Rats; D017208:Rats, Wistar; D013329:Structure-Activity Relationship; D000099252:Fatty Acid Amide Hydrolases
D000581:Amidohydrolases; D063385:Cannabinoid Receptor Modulators; D002219:Carbamates; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D008994:Monoacylglycerol Lipases; D010636:Phenols; D000099252:Fatty Acid Amide Hydrolases