Modulation of the Endocannabinoid System via Inhibition of Fatty Acid Amide Hydrolase (FAAH) by Novel Urea and Carbamate Derivatives

Abstract

AbstractRecent discoveries in the physiology and pharmacology of the endocannabinoid system (ECS) ushered in new therapeutic potential for the treatment of pain, inflammatory, sleep, eating, and various CNS disorders. To date, diverse synthetic molecules have been reported to target the cannabinoid (CB) receptors. While very potent, the exogenous agonists of CB receptors are often accompanied by adverse effects such as impaired memory, cognition, and most notably addiction. On the contrary, the known endogenous agonists such as anandamide (AEA) and 2‐arachidonoylglycerol (2‐AG) are susceptible to enzyme‐mediated hydrolysis thus are not feasible as therapeutic agents. Fatty acid amide hydrolase (FAAH) is the principal enzyme responsible for degradation of anandamide and related regulatory lipophilic molecules such as oleamide. Inhibition of FAAH potentiates the action of the endogenous CB agonists, thus provides an indirect approach to modulate the endocannabinoid system. This approach also eliminates the unwanted adverse effects observed with the use of direct synthetic CB agonists. An efficient one‐pot, two‐step synthetic protocol was used to prepare a focused library of lipophilic compounds with potential inhibitory activity of FAAH. Those molecules were screened in vitro and their activity was reported as percent (%) of enzyme's inhibition. Overall, several analogs showed 40% or greater inhibition of FAAH at 100 μM compound's concentration, and many of them also retained high activity at 50 μM compound's concentration. Those results imply that diacyl ureas, acyl ureas and acyl carbamates can serve as the starting point for medicinal chemistry structure optimization in search of novel inhibitors of FAAH.