Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake

Abstract

Significance Suitable chemical tools have been instrumental in the discovery and characterization of the endocannabinoid system. However, the lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process. Current uptake inhibitors are poorly bioavailable to the central nervous system (CNS) and weakly selective because they also inhibit fatty acid amide hydrolase (FAAH), the major anandamide-degrading enzyme. Few studies have addressed the uptake inhibition of 2-arachidonoyl glycerol (2-AG), which is the major endocannabinoid. Here, we report a highly potent and selective endocannabinoid reuptake inhibitor. Our data indicate that endocannabinoid transport across the membrane can be targeted, leading to general antiinflammatory and anxiolytic effects in mice.