The endogenous cannabinoids (endocannabinoids) are amides, esters and ethers of long chain polyunsaturated fatty acids. These lipids are bioactive signaling molecules that show diverse cellular and physiological effects and play various roles both in the central nervous system and in the periphery. The discovery 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 endocannabinoid tone and biological activity through inhibition of FAAH. Here we discuss the role of natural endocarmabinoid derivatives, like the hydroxy-anandam ides (OH-AEAs) generated from AEA via lipoxygenase activity, as powerful inhibitors of FAAH. We propose that these compounds, by reversibly inhibiting FAAH, may control in vivo the endocannabinoid tone. We discuss also the potential value of OH-AEAs as templates for the development of next-generation therapeutics that act at specific sites of FAAH.
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