Author/Authors :
Alvin R. King، نويسنده , , Andrea Duranti، نويسنده , , Andrea Tontini، نويسنده , , Silvia Rivara، نويسنده , , Anja Rosengarth، نويسنده , , Jason R. Clapper، نويسنده , , Giuseppe Astarita، نويسنده , , Jennifer A. Geaga، نويسنده , , Hartmut Luecke، نويسنده , , Marco Mor، نويسنده , , Giorgio Tarzia، نويسنده , , Daniele Piomelli، نويسنده ,
Abstract :
The N-aryl carbamate URB602 (biphenyl-3-ylcarbamic acid cyclohexyl ester) is an inhibitor of monoacylglycerol lipase (MGL), a serine hydrolase involved in the biological deactivation of the endocannabinoid 2-arachidonoyl-sn-glycerol (2-AG). Here, we investigated the mechanism by which URB602 inhibits purified recombinant rat MGL by using a combination of biochemical and structure-activity relationship (SAR) approaches. We found that URB602 weakly inhibits recombinant MGL (IC50 = 223 ± 63 μM) through a rapid and noncompetitive mechanism. Dialysis experiments and SAR analyses suggest that URB602 acts through a partially reversible mechanism rather than by irreversible carbamoylation of MGL. Finally, URB602 (100 μM) elevates 2-AG levels in hippocampal slice cultures without affecting levels of other endocannabinoid-related substances. Thus, URB602 may provide a useful tool by which to investigate the physiological roles of 2-AG and explore the potential interest of MGL as a therapeutic target.
