Journal
ACS CHEMICAL NEUROSCIENCE
Volume 4, Issue 9, Pages 1322-1332Publisher
AMER CHEMICAL SOC
DOI: 10.1021/cn400116z
Keywords
activity-based protein profiling; 2-arachidonoyl glycerol; carbamate; endocannabinoid; inhibitor; click chemistry; monoacylglycerol lipase
Funding
- National Institutes of Health [DA017259, DA033760, DA032933, DA032541]
- Skaggs Institute for Chemical Biology
- Biotechnology and Biological Sciences Research Council
- Abide Therapeutics
- MRC [MR/K00414X/1] Funding Source: UKRI
Ask authors/readers for more resources
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 enzymes 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available