Characterization of monoacylglycerol lipase inhibition reveals differences in central and peripheral endocannabinoid metabolism.

Monoacylglycerol lipase (MAGL) is a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). We recently reported a piperidine carbamate, JZL184, that inhibits MAGL with high potency and selectivity. Here, we describe a comprehensive mechanistic characterization of JZL184. We provide evidence that JZL184 irreversibly inhibits MAGL via carbamoylation of the enzyme's serine nucleophile. Functional proteomic analysis of mice treated with JZL184 revealed that this inhibitor maintains good selectivity for MAGL across a wide range of central and peripheral tissues. Interestingly, MAGL blockade produced marked, tissue-specific differences in monoglyceride metabolism, with brain showing the most dramatic elevations in 2-AG and peripheral tissues often showing greater changes in other monoglycerides. Collectively, these studies indicate that MAGL exerts tissue-dependent control over endocannabinoid and monoglyceride metabolism and designate JZL184 as a selective tool to characterize the functions of MAGL in vivo.