Format

Send to

Choose Destination
ACS Chem Neurosci. 2013 Sep 18;4(9):1322-32. doi: 10.1021/cn400116z. Epub 2013 Jun 17.

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

Author information

1
The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.

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.

PMID:
23731016
PMCID:
PMC3778430
DOI:
10.1021/cn400116z
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for American Chemical Society Icon for PubMed Central
Loading ...
Support Center