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URB602 Inhibits Monoacylglycerol Lipase and Selectively Blocks 2-Arachidonoylglycerol Degradation in Intact Brain Slices

  • Author(s): King, AR
  • Duranti, A
  • Tontini, A
  • Rivara, S
  • Rosengarth, A
  • Clapper, JR
  • Astarita, G
  • Geaga, JA
  • Luecke, H
  • Mor, M
  • Tarzia, G
  • Piomelli, D
  • et al.
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. © 2007 Elsevier Ltd. All rights reserved.

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