2. Academic Validation
  3. Selectivity of inhibitors of endocannabinoid biosynthesis evaluated by activity-based protein profiling

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

  • Bioorg Med Chem Lett. 2008 Nov 15;18(22):5838-41. doi: 10.1016/j.bmcl.2008.06.091.
Heather S Hoover 1,  Jacqueline L Blankman,  Sherry Niessen,  Benjamin F Cravatt
Affiliations

Affiliation

  • 1 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.
PMID: 18657971 DOI: 10.1016/j.bmcl.2008.06.091
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.

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