RESUMEN
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.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Moduladores de Receptores de Cannabinoides/metabolismo , Carbamatos/química , Endocannabinoides , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/farmacología , Monoacilglicerol Lipasas/antagonistas & inhibidores , Fenoles/química , Animales , Transporte Biológico/efectos de los fármacos , Línea Celular Tumoral , Electrones , Inhibidores Enzimáticos/química , Humanos , Hidrólisis/efectos de los fármacos , Masculino , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Fatty acid amide hydrolase (FAAH) is an intracellular serine hydrolase, which catalyzes the hydrolysis of the endocannabinoid N-arachidonoylethanolamide to arachidonic acid and ethanolamine. FAAH also hydrolyzes another endocannabinoid, 2-arachidonoylglycerol (2-AG). However, 2-AG has been assumed to be hydrolyzed mainly by monoacylglycerol lipase (MAGL) or a MAGL-like enzyme. Inhibition of FAAH or MAGL activity might lead to beneficial effects in many physiological disorders such as pain, inflammation, and anxiety due to increased endocannabinoid-induced activation of cannabinoid receptors CB1 and CB2. In the present study, a total of 34 novel compounds were designed, synthesized, characterized, and tested against FAAH and MAGL-like enzyme activity. Altogether, 16 compounds were found to inhibit FAAH with half-maximal inhibition concentrations (IC50) between 28 and 380 nM. All the active compounds belong to the structural family of carbamates. Compounds 14 and 18 were found to be the most potent FAAH inhibitors, which may serve as lead structures for novel FAAH inhibitors.
Asunto(s)
Amidohidrolasas/antagonistas & inhibidores , Benzamidas/síntesis química , Benzotiazoles/síntesis química , Benzoxazoles/síntesis química , Carbamatos/síntesis química , Animales , Benzamidas/química , Benzamidas/farmacología , Benzotiazoles/química , Benzotiazoles/farmacología , Benzoxazoles/química , Benzoxazoles/farmacología , Encéfalo/metabolismo , Carbamatos/química , Carbamatos/farmacología , Diseño de Fármacos , Técnicas In Vitro , Masculino , Monoacilglicerol Lipasas/antagonistas & inhibidores , Ratas , Ratas Wistar , Relación Estructura-ActividadRESUMEN
Alpha-methylated analogues of the endogenous cannabinoid, 2-arachidonoyl glycerol (2-AG), were synthesized aiming to the improved enzymatic stability of 2-AG. In addition, the CB1 activity properties of fluoro derivatives of 2-AG were studied. The CB1 receptor activity was determined by the [35S]GTPgammaS binding assay, and the enzymatic stability of alpha-methylated analogues was determined in rat cerebellar membranes. The results indicate that even if the alpha-methylated 2-AG derivatives are slightly weaker CB1 receptor agonists than 2-AG, they are clearly more stable than 2-AG. In addition, the results showed that the replacement of the hydroxyl group(s) of 2-AG by fluorine does not improve the CB1 activity of 2-AG.