Overview of the Chemical Families of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase Inhibitors

The family of the endogenous agonists of the cannabinoid receptors - i.e., the endocannabinoids - includes several polyunsaturated fatty acid amides and esters. Arachidonoylethanolamide (anandamide, AEA) and 2-arachidonoylglycerol (2-AG) are, respectively, the leads of these chemical families. So far, two enzymes responsible for the metabolism of AEA and 2-AG have been described: Fatty Acid Amide Hydrolase (FAAH) which hydrolyzes AEA and in some cells 2-AG, and Monoacylglycerol Lipase (MAGL) which hydrolyzes 2-AG. In spite of the early characterisation of MAGL and the nearly simultaneous clonings of the two enzymes, most of the efforts were dedicated to the study of FAAH and consequentially, the range of FAAH inhibitors available nowadays exceeds the number of compounds active upon MAGL. FAAH inhibitors can be divided in two major groups, the first one includes the inhibitors inspired by the chemical structures of FAAH substrates, which carry an arachidonoyl-, oleoyl- or palmitoyl-carbon chain that mimic the fatty acid chains of anandamide, oleamide and palmitoylethanolamide. The second group involves compounds that do not share similarities with the endocannabinoids, such as the carbamates, oxazolopyridins, 2-thioxoimidazolidin-4-ones, imidazolidine-2,4-diones and the non-steroidal anti-inflammatory drugs. However, the family of MAGL inhibitors contains few members and most of them exhibit a lack of selectivity. The purpose of this review is to give an overview of the families of synthetic inhibitors of FAAH and MAGL. The synthetic pathways, the chemical features, potencies, selectivities and modes of inhibition are listed and discussed in order to facilitate their comparison.