Natural Compounds and Synthetic Drugs to Target FAAH Enzyme

The fatty acid amide hydrolase (FAAH) executes a unique role in terminating endocannabinoid signaling, and is the major regulator of anadamide catabolism in vivo. Inhibition of FAAH elicits indirect agonism on cannabinoid receptors, and therapeutic efficacy, devoid of psychotropic effects. This supports its relevance as an attractive therapeutic target. Great efforts in the medicinal chemistry, biochemistry, and crystallography fields have synergistically provided pivotal information key to the production of a number of inhibitors, characterized by different structures and mechanisms of action, for attaining FAAH inhibition. As the knowledge about the enzyme structure and functioning grew, in the past two decades, the developed compounds became more specific and structurally different from the natural substrates, thus allowing better selectivity and inhibition potency to be attained. This was pivotal for the identification of leads and druggable compounds to be clinically exploited for the treatment of a number of diseases. The lesson learned by the tragic outcome of the clinical studies with BIA 10-2474 have drawn a clear trajectory for pre-clinical assessment of off-target liabilities, while offering a chance to clearly outline the safety of FAAH as a drug target. A number of natural compounds from mammalian and vegetal sources have been identified so far and have been characterized as FAAH inhibitors and modulators. These compounds may inspire the design of further effective FAAH inhibitors that encompass the enzyme physiological functioning and enzyme trafficking. This issue may offer a new view that considers the crucial events that regulate substrates and compounds accessibility to the FAAH catalytic site and that may affect in vivo efficacy. © The Royal Society of Chemistry 2021