Evaluation of NHS Carbamates as a Potent and Selective Class of Endocannabinoid Hydrolase Inhibitors
Open accessAbstract
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.
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FAAH and MAGL inhibitors reduce nociceptive behavior in STZ-injected rats.
“In addition, FAAH (Hasanein et al, 2009;Sasso et al, 2015) and MAGL (Niphakis et al, 2013) inhibitors reduce nociceptive behavior in STZ-injected rats.”
From The endogenous cannabinoid system: a budding source of targets for treating inflammatory and neuropathic pain (2018) · cites this paper as Niphakis et al, 2013
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- Authors
- Niphakis, M. J., Cognetta, A. B., Chang, J. W., Buczynski, M. W., Parsons, L. H., Byrne, F., Burston, J. J., Chapman, V., & Cravatt, B. F.
- Affiliations
- Scripps Research Institute (US)
- University of Nottingham (GB)
- Corresponding author
- Niphakis, Micah J.
- Cravatt, Benjamin F.
- ORCID
- Venue
- ACS Chemical Neuroscience
- Publisher
- American Chemical Society (ACS)
- Published
- 2013-06-17
- Volume
- 4
- Issue
- 9
- Pages
- 1322-1332
- ISSN
- 1948-7193 (ISSN-L)
- PMC
- PMC3778430
- OpenAlex
- W2040580317
- Cited by
- 157
- References
- 57
- Citations by year
- 2026: 15 · 2025: 8 · 2024: 10 · 2023: 13 · 2022: 11 · 2021: 23 · 2020: 10 · 2019: 11 · 2018: 15 · 2017: 9 · 2016: 11 · 2015: 12 · 2014: 8 · 2013: 1
- FWCI
- 8.08
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- ACS Chemical Neuroscience (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- ORCA Online Research @Cardiff (Cardiff University) (acceptedVersion)
- Funders
- National Institutes of Health (DA017259)
- Directorate for Biological Sciences
- Biotechnology and Biological Sciences Research Council
- National Institute on Alcohol Abuse and Alcoholism (R01AA020404)
- National Institute on Drug Abuse (DA033760, F32DA032541, DA-017259, DA032933, R01DA032933, R01DA033760, P01DA017259, F32DA029994, DA032541)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Enzyme function and inhibition
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Eicosanoids and Hypertension Pharmacology
- Keywords
- monoacylglycerol lipase, MAGL inhibitors, 2-arachidonoylglycerol, serine hydrolase inhibitors, mechanical allodynia, diabetic neuropathy, in vivo enzyme inhibition
- MeSH terms
- Fatty Acid Amide Hydrolases, Amidohydrolases, Animals, Blood Glucose, Brain, Carbamates, Diabetes Mellitus, Type 2, Diabetic Neuropathies, Drug Evaluation, Preclinical, Humans, Hyperalgesia, Insulin, Liver, Male, Monoacylglycerol Lipases, Species Specificity, Structure-Activity Relationship, Succinimides, Molecular Structure, Rats, Sprague-Dawley, Mice, Rats, HEK293 Cells, Nociception, Endocannabinoids
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