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Background and purpose: Two compounds, URB602 and URB754, have been reported in the literature to be selective inhibitors of monoacylglycerol lipase, although a recent study has questioned their ability to prevent 2‐arachidonoyl hydrolysis by brain homogenates and cerebellar membranes. In the present study, the ability of these compounds to inhibit monoacylglycerol lipase and fatty acid amide hydrolase has been reinvestigated. Experimental approach: Homogenates and cell lines were incubated with test compounds and, thereafter, with either [3H]‐2‐oleoylglycerol or [3H]‐anandamide. Labelled reaction products were separated from substrate using chloroform: methanol extraction. Key results: In cytosolic fractions from rat brain, URB602 and URB754 inhibited the hydrolysis of 2‐oleoylglycerol with IC50 values of 25 and 48 μM, respectively. Anandamide hydrolysis by brain membranes was not sensitive to URB754, but was inhibited by URB602 (IC50 value 17 μM). Hydrolysis of 2‐oleoylglycerol by human recombinant monoacylglycerol lipase was sensitive to URB602, but not URB754. The lack of selectivity of URB602 for 2‐oleoylglycerol compared to anandamide hydrolysis was also observed for intact RBL2H3 basophilic leukaemia cells. C6 glioma expressed mRNA for monoacylglycerol lipase, and hydrolyzed 2‐oleoylglycerol in a manner sensitive to inhibition by methyl arachidonoyl fluorophosphonate but not URB754 or URB597. MC3T3‐E1 mouse osteoblastic cells, which did not express mRNA for monoacylglycerol lipase, hydrolyzed 2‐oleoylglycerol in the presence of URB597, but the hydrolysis was less sensitive to methyl arachidonoyl fluorophosphonate than for C6 cells. Conclusions and implications: The data demonstrate that the compounds URB602 and URB754 do not behave as selective and/or potent inhibitors of monoacylglycerol lipase. British Journal of Pharmacology (2007) 150, 186–191. doi:10.1038/sj.bjp.0706971

Background and purpose: Cerebrovascular smooth muscle cells express the CB1 cannabinoid receptor and CB1 agonists produce vasodilatation of the middle cerebral artery (MCA). The thromboxane A2 mimetic, U‐46619, increased the content of the endocannabinoid, 2‐arachidonoylglycerol (2‐AG) in the MCA and 2‐AG moderated the vasoconstriction produced by U46619 in this tissue. The purposes of this study were to examine the extent to which 2‐AG is catabolized by cerebral arteries and to determine whether blockade of 2‐AG inactivation potentiates its feedback inhibition of U‐44619‐mediated vasoconstriction. Experimental approach: The diameters of isolated, perfused MCA from male rats were measured using videomicroscopy. Key results: Exogenous 2‐AG produces a CB1 receptor‐dependent and concentration‐related increase in the diameter of MCA constricted with 5‐HT. The E max for 2‐AG dilation is increased 4‐fold in the presence of the metabolic inhibitors 3‐(decylthio)‐1,1,1‐trifluropropan‐2‐one (DETFP), URB754 and URB597. To examine the role of catabolism in the effects of endogenous 2‐AG, vasoconstriction induced by U‐46619 was studied. DETFP and URB754, but not the fatty acid amide hydrolase inhibitor, URB597, significantly increased the EC50 for U‐46619. These data support a physiological role for endocannabinoid feedback inhibition in the effects of U‐46619 and indicate that endogenously produced 2‐AG is also efficiently catabolized within the MCA. Conclusions and implications: MCA express mechanisms for the efficient inactivation of 2‐AG, providing further support for an endocannabinoid feedback mechanism that opposes thromboxane‐mediated vasoconstriction. These data suggest that potentiation of endogenously produced 2‐AG could be a novel therapeutic approach to the treatment of thrombotic stroke. British Journal of Pharmacology (2007) 152, 691–698; doi:10.1038/sj.bjp.0707468; published online 24 September 2007