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Bioorg Med Chem Lett. 2011 Dec 15;21(24):7321-4. doi: 10.1016/j.bmcl.2011.10.026. Epub 2011 Oct 18.

Benzisothiazolinone as a useful template for the design of new monoacylglycerol lipase inhibitors: investigation of the target residues and comparison with octhilinone.

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Université catholique de Louvain, Louvain Drug Research Institute, Medicinal Chemistry Department (CMFA), 73 Avenue E. Mounier, bte B1.73.10, B-1200 Bruxelles, Belgium.


The regulation of 2-arachidonoylglycerol (2-AG) levels is a major issue as 2-AG has been proven to participate in numerous physiopathological phenomena such as neuroprotection or analgesia. Octhilinone, a cysteine-reagent compound, has recently been shown to inhibit in the nanomolar range monoacylglycerol lipase (MAGL), the major enzyme responsible for the degradation of 2-AG. Here, we further investigate the mechanism by which octhilinone and its benzisothiazolinone analog inhibit human MAGL. We also provide new information on the structural requirements for MAGL inhibition by these compounds. Finally, we describe for N-octylbenzisothiazolinone a mode of inhibition which is partially different from that described for octhilinone, especially with regard to the targeted cysteine residues in the vicinity of the catalytic site.

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