Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling

The endocannabinoid 2- arachidonoylglycerol (2- AG) has been implicated as a key retrograde mediator in the nervous system based on pharmacological studies using inhibitors of the 2- AG biosynthetic enzymes diacyglycerol lipase alpha and beta (DAGL-alpha/beta). Here, we show by competitive activity-based protein profiling that the DAGL-alpha/beta inhibitors, tetrahydrolipstatin (THL) and RHC80267, block several brain serine hydrolases with potencies equal to or greater than their inhibitory activity against DAGL enzymes. Interestingly, a minimal overlap in target profiles was observed for THL and RHC80267, suggesting that pharmacological effects observed with both agents may be viewed as good initial evidence for DAGL-dependent events. (C) 2008 Elsevier Ltd. All rights reserved.