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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Arachidonic Acids / antagonists & inhibitors*
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Arachidonic Acids / biosynthesis*
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Brain / enzymology*
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Cannabinoid Receptor Modulators / antagonists & inhibitors*
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Cannabinoid Receptor Modulators / biosynthesis*
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Cyclohexanones / pharmacology*
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Endocannabinoids*
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Glycerides / antagonists & inhibitors*
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Glycerides / biosynthesis*
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Humans
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Isoenzymes / antagonists & inhibitors
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Lactones / pharmacology*
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Lipase / antagonists & inhibitors*
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Molecular Structure
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Orlistat
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Receptor, Cannabinoid, CB1 / metabolism
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Serine Proteinase Inhibitors / pharmacology*
Substances
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Arachidonic Acids
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Cannabinoid Receptor Modulators
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Cyclohexanones
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Endocannabinoids
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Glycerides
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Isoenzymes
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Lactones
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Receptor, Cannabinoid, CB1
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Serine Proteinase Inhibitors
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1,6-bis(cyclohexyloximinocarbonyl)hexane
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glyceryl 2-arachidonate
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Orlistat
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Lipase