Carbamates with <i>ortho</i>-Substituted <i>O</i>-Phenyl Groups as Dual Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: Inhibitory Potency, Hydrolytic Stability, and QSAR Studies

The serine hydrolases fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) are key enzymes in the degradation of endocannabinoids, which regulate numerous physiological processes. Their role in maintaining endocannabinoid balance makes them promising targets for treating neurological disorders. We synthesized a series of 6-(5-phenyltetrazolylhexyl)-carbamates bearing <i>O</i>-phenyl residues with various <i>ortho</i>-substituents. Inhibition of FAAH and MAGL was found to depend on the inductive and electronic properties of these substituents. Electron-withdrawing groups increase carbamate reactivity, promoting faster covalent bonding with the catalytic serine in the enzymes' active sites. However, this also raises the compounds' susceptibility to hydrolysis. Quantitative structure-activity relationship (QSAR) analysis revealed a strong logarithmic correlation between FAAH inhibition of compounds with uncharged <i>ortho</i>-substituents, expressed as logIC₅₀, and the electron-withdrawing effect of theses residues, measured by the Hammett sigma (σ) constant. Conversely, this correlation allows estimation of unknown Hammett constants from the FAAH inhibition data of suitably substituted carbamates.