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

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