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-snglycerol (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 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.

URB602 inhibits monoacylglycerol lipase and selectively blocks 2-arachidonoylglycerol degradation in intact brain slices / King, A. R.; Duranti, A.; Tontini, A.; Rivara, Silvia; Rosengarth, A.; Clapper, J. R.; Astarita, G.; Geaga, J. A.; Luecke, H.; Mor, Marco; Tarzia, G.; Piomelli, D.. - In: CHEMISTRY & BIOLOGY. - ISSN 1074-5521. - 14:(2007), pp. 1357-1365. [10.1016/j.chembiol.2007.10.017]

URB602 inhibits monoacylglycerol lipase and selectively blocks 2-arachidonoylglycerol degradation in intact brain slices.

RIVARA, Silvia;MOR, Marco;
2007-01-01

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-snglycerol (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 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.
2007
URB602 inhibits monoacylglycerol lipase and selectively blocks 2-arachidonoylglycerol degradation in intact brain slices / King, A. R.; Duranti, A.; Tontini, A.; Rivara, Silvia; Rosengarth, A.; Clapper, J. R.; Astarita, G.; Geaga, J. A.; Luecke, H.; Mor, Marco; Tarzia, G.; Piomelli, D.. - In: CHEMISTRY & BIOLOGY. - ISSN 1074-5521. - 14:(2007), pp. 1357-1365. [10.1016/j.chembiol.2007.10.017]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/1723266
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