In vitro activity: JZL195 is a potent, selective and efficacious dual FAAH/MAGL (fatty acid amide hydrolase/monoacylglycerol lipase) inhibitor with IC50 of 13 nM and 19 nM for mouse brain FAAH and MAGL respectively. JZL195 exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. In addition, JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects. in vitro: JZL195 shows only modest and incomplete inhibitory activity against NTE (IC50>5 uM). At higher concentrations, JZL195 inhibited ABHD6 but not any of the other brain serine hydrolases detected in our competitive ABPP assays. JZL195 also inhibited rat and human FAAH and MAGL enzymes with IC50 values in the range of 10–100 nM based on competitive ABPP assays

Kinase Assay: JZL195 is a potent, selective and efficacious dual FAAH/MAGL (fatty acid amide hydrolase/monoacylglycerol lipase) inhibitor with IC50 of 13 nM and 19 nM for mouse brain FAAH and MAGL respectively. JZL195 exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist.

Cell Assay: JZL195 is a potent, selective and efficacious dual FAAH/MAGL (fatty acid amide hydrolase/monoacylglycerol lipase) inhibitor with IC50 of 13 nM and 19 nM for mouse brain FAAH and MAGL respectively. JZL195 exhibits broad activity in the tetrad test for CB1 agonism, causing analgesia, hypomotilty, and catalepsy. Comparison of JZL195 to specific FAAH and MAGL inhibitors identified behavioral processes that were regulated by a single endocannabinoid pathway (e.g., hypomotility by the 2-AG/MAGL pathway) and, interestingly, those where disruption of both FAAH and MAGL produced additive effects that were reversed by a CB1 antagonist. In addition, JZL195 reduces inflammation induced allodynia at doses below those which produce side-effects, and displays greater efficacy that FAAH or MAGL inhibitors. Thus, dual FAAH/MAGL inhibition has the potential to alleviate inflammatory pain with reduced cannabinoid-like side-effects.