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Hoover, Heather S.; Blankman, Jacqueline L.; Niessen, Sherry; Cravatt, Benjamin F.
Bioorganic & medicinal chemistry, 11/2008, Volume: 18, Issue: 22Journal Article
Functional proteomic profiling reveals several brain hydrolase targets for endocannabinoid biosynthesis inhibitors. 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 α and β (DAGL-α/β). Here, we show by competitive activity-based protein profiling that the DAGL-α/β 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.
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