Carbamoyl tetrazoles as inhibitors of endocannabinoid inactivation: A critical revisitation

Equipotent Inhibition of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase – Dual Targets of the Endocannabinoid System to Protect against Seizure Pathology

“…AM6701 is a regioisomer of AM6702, a compound that does not exhibit synergistic action on the 2 enzymes. In fact, AM6702 was found to have near equipotency for the inhibition of FAAH and AEA transport [64], suggesting the compound has a focused effect on AEA tone. On the other hand, the dual modulation of AM6701 of AEA and 2-AG tone by targeting both FAAH and MAGL may point to a reparative synergy.…”

“…AM6701 efficiently inhibits the endocannabinoid-deactivating enzymes, AM6701 being 24-fold more potent than AM6702 regarding its action on MAGL. Others have found AM6701 to be even more potent than AM6702 regarding its action on 2-AG catabolism [42,64]. Potent inhibition of MAGL by AM6701 is thought to be due to the covalent carbamylation of serine-122 in MAGLs catalytic triad characteristic of serine hydrolases [42].…”

Chemical Probes of Endocannabinoid Metabolism

“…One of the earliest urea-based FAAH inhibitors, LY-2183240 (Fig. 5A), was originally described as an inhibitor of the putative anandamide transporter (Moore et al, 2005), but was later found to potently block FAAH and several other brain serine hydrolases by ABPP (Alexander and and substrate (Ortar et al, 2008) assays. Treatment of rats with LY-2183240 raised brain anandamide levels ;5-fold and alleviated formalininduced pain behaviors without affecting motor coordination (Moore et al, 2005).…”

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…3,89 Indeed, a 2,5-regioisomer of 50 (compound 143, Figure 51) exhibited approximately 400 times more potent inhibition against MAGL-like enzyme in comparison to 50 (IC50 = 0.02 and 8.10 µM, respectively). 151 Unfortunately, compound 143 exerted poor selectivity over FAAH expressed in rat brain membranes (IC50 = 0.033 µM). The investigation of its binding mechanism by mass spectrometry and mutational analysis showed that the hydroxyl group of Ser122 interacted with the urea moiety of 143 to produce a carbamylated-enzyme adduct, accompanied by the release of the biphenylmethyl tetrazole moiety ( Figure 52).…”