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Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors.
- Source :
-
ACS chemical neuroscience [ACS Chem Neurosci] 2013 Sep 18; Vol. 4 (9), pp. 1322-32. Date of Electronic Publication: 2013 Jun 17. - Publication Year :
- 2013
-
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.
- Subjects :
- Animals
Blood Glucose analysis
Brain drug effects
Brain enzymology
Carbamates chemical synthesis
Carbamates chemistry
Carbamates therapeutic use
Diabetes Mellitus, Type 2 blood
Diabetes Mellitus, Type 2 complications
Diabetic Neuropathies blood
Diabetic Neuropathies drug therapy
Drug Evaluation, Preclinical
HEK293 Cells
Humans
Hyperalgesia drug therapy
Insulin blood
Liver drug effects
Liver enzymology
Male
Mice
Molecular Structure
Nociception drug effects
Rats
Rats, Sprague-Dawley
Species Specificity
Structure-Activity Relationship
Succinimides chemistry
Succinimides therapeutic use
Amidohydrolases antagonists & inhibitors
Carbamates pharmacology
Endocannabinoids metabolism
Monoacylglycerol Lipases antagonists & inhibitors
Succinimides pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1948-7193
- Volume :
- 4
- Issue :
- 9
- Database :
- MEDLINE
- Journal :
- ACS chemical neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 23731016
- Full Text :
- https://doi.org/10.1021/cn400116z