title: Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling.
abstract: 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.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute, 10550 N. Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Heather S
authors.initials: HS
authors.lastname: Hoover
authors.forename: Jacqueline L
authors.initials: JL
authors.lastname: Blankman
authors.forename: Sherry
authors.initials: S
authors.lastname: Niessen
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D001921:Brain / Q000201:enzymology*; D063385:Cannabinoid Receptor Modulators / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D003512:Cyclohexanones / Q000494:pharmacology*; D063388:Endocannabinoids; D005989:Glycerides / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D007783:Lactones / Q000494:pharmacology*; D008049:Lipase / Q000037:antagonists & inhibitors*; D015394:Molecular Structure; D000077403:Orlistat; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D003512:Cyclohexanones; D063388:Endocannabinoids; D005989:Glycerides; D007527:Isoenzymes; D007783:Lactones; D043884:Receptor, Cannabinoid, CB1; D015842:Serine Proteinase Inhibitors; C036535:1,6-bis(cyclohexyloximinocarbonyl)hexane; C094503:glyceryl 2-arachidonate; D000077403:Orlistat; D008049:Lipase