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Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates.


ABSTRACT: The endocannabinoids 2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide) are principally degraded by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. The recent discovery of O-aryl carbamates such as JZL184 as selective MAGL inhibitors has enabled functional investigation of 2-AG signaling pathways in vivo. Nonetheless, JZL184 and other reported MAGL inhibitors still display low-level cross-reactivity with FAAH and peripheral carboxylesterases, which can complicate their use in certain biological studies. Here, we report a distinct class of O-hexafluoroisopropyl (HFIP) carbamates that inhibits MAGL in vitro and in vivo with excellent potency and greatly improved selectivity, including showing no detectable cross-reactivity with FAAH. These findings designate HFIP carbamates as a versatile chemotype for inhibiting MAGL and should encourage the pursuit of other serine hydrolase inhibitors that bear reactive groups resembling the structures of natural substrates.

SUBMITTER: Chang JW 

PROVIDER: S-EPMC3361572 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Highly selective inhibitors of monoacylglycerol lipase bearing a reactive group that is bioisosteric with endocannabinoid substrates.

Chang Jae Won JW   Niphakis Micah J MJ   Lum Kenneth M KM   Cognetta Armand B AB   Wang Chu C   Matthews Megan L ML   Niessen Sherry S   Buczynski Matthew W MW   Parsons Loren H LH   Cravatt Benjamin F BF  

Chemistry & biology 20120426 5


The endocannabinoids 2-arachidonoyl glycerol (2-AG) and N-arachidonoyl ethanolamine (anandamide) are principally degraded by monoacylglycerol lipase (MAGL) and fatty acid amide hydrolase (FAAH), respectively. The recent discovery of O-aryl carbamates such as JZL184 as selective MAGL inhibitors has enabled functional investigation of 2-AG signaling pathways in vivo. Nonetheless, JZL184 and other reported MAGL inhibitors still display low-level cross-reactivity with FAAH and peripheral carboxylest  ...[more]

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