| Literature DB >> 18096504 |
Alvin R King1, Andrea Duranti, Andrea Tontini, Silvia Rivara, Anja Rosengarth, Jason R Clapper, Giuseppe Astarita, Jennifer A Geaga, Hartmut Luecke, Marco Mor, Giorgio Tarzia, Daniele Piomelli.
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 (IC(50) = 223 +/- 63 microM) 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 microM) 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.Entities:
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Year: 2007 PMID： 18096504 PMCID： PMC2225625 DOI： 10.1016/j.chembiol.2007.10.017
Source DB: PubMed Journal: Chem Biol ISSN： 1074-5521