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PMID: 18657971 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Bioorganic & medicinal chemistry letters ·Vol. 18 ·No. 22 ·2008-11-15 ·Pages 5838-41

Hoover HS, Blankman JL, Niessen S, Cravatt BF

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.

MeSH Terms
Arachidonic Acids/antagonists & inhibitors,biosynthesis Brain/enzymology Cannabinoid Receptor Modulators/antagonists & inhibitors,biosynthesis Cyclohexanones/pharmacology Endocannabinoids Glycerides/antagonists & inhibitors,biosynthesis Humans Isoenzymes/antagonists & inhibitors Lactones/pharmacology Lipase/antagonists & inhibitors Molecular Structure Orlistat Receptor, Cannabinoid, CB1/metabolism Serine Proteinase Inhibitors/pharmacology
Chemicals
Arachidonic Acids Cannabinoid Receptor Modulators Cyclohexanones Endocannabinoids Glycerides Isoenzymes Lactones Receptor, Cannabinoid, CB1 Serine Proteinase Inhibitors 1,6-bis(cyclohexyloximinocarbonyl)hexane glyceryl 2-arachidonate Orlistat Lipase
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Hoover Heather S
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.
Blankman Jacqueline L
Niessen Sherry
Cravatt Benjamin F
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Article Info
Journal
Bioorganic & medicinal chemistry letters
Abbr.
Bioorg Med Chem Lett
ISSN
1464-3405
DOI
10.1016/j.bmcl.2008.06.091
Published
2008-11-15
Epub
2008-00-02
Pages
5838-41
Language
English
Region
England
NLM ID
9107377
PMCID
PMC2634297
Subset
IM
Grants
NIDA NIH HHS · P01 DA017259-05 · United States
NIDA NIH HHS · R01 DA025285 · United States
NIDA NIH HHS · DA025285 · United States
NIDA NIH HHS · R01 DA025285-01 · United States
NIDA NIH HHS · DA017259 · United States
NIDA NIH HHS · P01 DA017259 · United States
External Links
PubMed source DOI: 10.1016/j.bmcl.2008.06.091 PMC Full Text View journal details
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