title: Evaluation of NHS carbamates as a potent and selective class of endocannabinoid hydrolase inhibitors.
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.
authors.affiliation: The Skaggs Institute for Chemical Biology and Department of Chemical Physiology, The Scripps Research Institute , La Jolla, California 92037, United States.
authors.forename: Micah J
authors.initials: MJ
authors.lastname: Niphakis
authors.forename: Armand B
authors.initials: AB
authors.lastname: Cognetta
authors.forename: Jae Won
authors.initials: JW
authors.lastname: Chang
authors.forename: Matthew W
authors.initials: MW
authors.lastname: Buczynski
authors.forename: Loren H
authors.initials: LH
authors.lastname: Parsons
authors.forename: Frederika
authors.initials: F
authors.lastname: Byrne
authors.forename: James J
authors.initials: JJ
authors.lastname: Burston
authors.forename: Victoria
authors.initials: V
authors.lastname: Chapman
authors.forename: Benjamin F
authors.initials: BF
authors.lastname: Cravatt
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors*; D000818:Animals; D001786:Blood Glucose / Q000032:analysis; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D002219:Carbamates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000150:complications; D003929:Diabetic Neuropathies / Q000097:blood / Q000188:drug therapy; D004353:Drug Evaluation, Preclinical; D063388:Endocannabinoids / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D006930:Hyperalgesia / Q000188:drug therapy; D007328:Insulin / Q000097:blood; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008297:Male; D051379:Mice; D015394:Molecular Structure; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D059225:Nociception / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013045:Species Specificity; D013329:Structure-Activity Relationship; D013388:Succinimides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D001786:Blood Glucose; D002219:Carbamates; D063388:Endocannabinoids; D007328:Insulin; D008994:Monoacylglycerol Lipases; D013388:Succinimides; D000099252:Fatty Acid Amide Hydrolases; C587715:MJN110; C587716:MJN110yne; C001426:N-hydroxysuccinimide