Natural Endocannabinoid Derivatives as Templates for the Development of FAAH Inhibitors

The endogenous cannabinoids (endocannabinoids) are amides, esters and ethers of long chainpolyunsaturated fatty acids. These lipids are bioactive signaling molecules that show diverse cellular andphysiological effects and play various roles both in the central nervous system and in the periphery. Thediscovery of N-arachidonoylethanolamine (anandamide, AEA) and of the enzyme that terminates its signaling,i.e. fatty acid amide hydrolase (FAAH), have inspired pharmacological strategies to augment endocannabinoidtone and biological activity through inhibition of FAAH. Here we discuss the role of natural endocannabinoidderivatives, like the hydroxy-anandamides (OH-AEAs) generated from AEA via lipoxygenase activity, aspowerful inhibitors of FAAH. We propose that these compounds, by reversibly inhibiting FAAH, may controlin vivo the endocannabinoid tone. We discuss also the potential value of OH-AEAs as templates for thedevelopment of next-generation therapeutics that act at specific sites of FAAH.[...]