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Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors

Niphakis, Micah J., Cognetta, Armand B., Chang, Jae Won, Buczynski, Matthew W., Parsons, Loren H., Byrne, Frederika, Burston, James J., Chapman, Victoria and Cravatt, Benjamin F. 2013. Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors. ACS Chemical Neuroscience 4 (9) , pp. 1322-1332. 10.1021/cn400116z

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Abstract

Monoacylglycerol lipase (MAGL) is a principal metabolic enzyme responsible for hydrolyzing the endogenous cannabinoid (endocannabinoid) 2-arachidonoylglycerol (2-AG). Selective inhibitors of MAGL offer valuable probes to further understand the enzyme’s function in biological systems and may lead to drugs for treating a variety of diseases, including psychiatric disorders, neuroinflammation, and pain. N-Hydroxysuccinimidyl (NHS) carbamates have recently been identified as a promising class of serine hydrolase inhibitors that shows minimal cross-reactivity with other proteins in the proteome. Here, we explore NHS carbamates more broadly and demonstrate their potential as inhibitors of endocannabinoid hydrolases and additional enzymes from the serine hydrolase class. We extensively characterize an NHS carbamate 1a (MJN110) as a potent, selective, and in-vivo-active MAGL inhibitor. Finally, we demonstrate that MJN110 alleviates mechanical allodynia in a rat model of diabetic neuropathy, marking NHS carbamates as a promising class of MAGL inhibitors.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Publisher: American Chemical Society
ISSN: 1948-7193
Last Modified: 04 Jul 2018 14:18
URI: http://orca.cardiff.ac.uk/id/eprint/112067

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