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).1 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.1 The in vivo inhibitory actions of JZL 195 against FAAH and MAGL are comparable to those of the selective inhibitors PF-3845 (Catalog No. 13279) and JZL 184 (Catalog No. 13158), respectively.1 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.1
1
Long, J.Z., Nomura, D.K., Vann, R.E., et al. Dual blockade of FAAH and MAGL identifies behavioral processes regulated by endocannabinoid crosstalk in vivo. Proc Natl Acad Sci USA106(48)20270-20275(2009).