Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) mediate the hydrolysis of the endocannabinoids arachidonoyl ethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), respectively. JZL 195 is a potent inhibitor of both FAAH and MAGL (IC50 = 2 and 4 nM, respectively). It poorly inhibits neuropathy target esterase and ABHD6 and does not inhibit other brain serine hydrolases. JZL 195 displays time-dependent inhibition of FAAH and MAGL in vivo, consistent with a covalent mechanism of activation. The in vivo inhibitory actions of JZL 195 against FAAH and MAGL are comparable to those of the selective inhibitors PF-3845 and JZL 184 , respectively. Through its inhibitory actions, JZL 195 simultaneously augments brain levels of AEA and 2-AG, producing antinociceptive, cataleptic, and hypomotility effects like those produced by direct CB1 agonists.
