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

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 b...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Veröffentlicht in:Bioorganic & medicinal chemistry 2008-11, Vol.18 (22), p.5838-5841
Hauptverfasser: Hoover, Heather S., Blankman, Jacqueline L., Niessen, Sherry, Cravatt, Benjamin F.
Format: Artikel
Sprache:eng
Schlagworte:
Online-Zugang:Volltext
Tags: Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
Beschreibung
Zusammenfassung: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.
ISSN:0960-894X
0968-0896
1464-3405
1464-3391
DOI:10.1016/j.bmcl.2008.06.091