1: Curr Top Med Chem. 2008;8(3):247-67.

Overview of the chemical families of fatty acid amide hydrolase and
monoacylglycerol lipase inhibitors.

Vandevoorde S.

National Institute for Radioelements, Department of Research and Development,
Bâtiment 3, Avenue de l'Espérance, B-6220 Fleurus, Belgium. generalmail@ire.be

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-arachidon-oylglycerol (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.


PMID: 18289091 [PubMed - indexed for MEDLINE]

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