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 IC50 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 IC50 values at the low-nanomolar (IC50s; 0.0063 and 0.012 mM) and the low-micromolar ranges (IC50s; 2.1 and 1.0 mM), respectively. Compound 26 also inhibited both FAAH-dependent AEA uptake and AEA hydrolysis (IC50; 0.082 mM) by intact RBL2H3 cells, and could also reduce 2-AG hydrolysis by these cells at concentrations 0.030 mM.