Highly Selective Inhibitors of Monoacylglycerol Lipase Bearing a Reactive Group that Is Bioisosteric with Endocannabinoid Substrates

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• 作者：Jae  ; Won Chang¹ ; ³ ; Micah  ; J. Niphakis¹ ; ³ ; ^{mniphak@scripps.edu} ; Kenneth  ; M. Lum¹ ; Armand  ; B. Cognetta III¹ ; Chu Wang¹ ; Megan  ; L. Matthews¹ ; Sherry Niessen¹ ; Matthew  ; W. Buczynski² ; Loren  ; H. Parsons² ; Benjamin  ; F. Cravatt¹ ; ^{cravatt@scripps.edu}
• 刊名：Chemistry & Biology
• 出版年：2012
• 期刊代码：20_10745521
• 类别：ch
• 出版时间：25 May, 2012
• 卷：19
• 期：5
• 页码：579-588
• 文件大小：1596 K

摘要

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Summary

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聽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聽O-hexafluoroisopropyl (HFIP) carbamates that inhibits MAGL in聽vitro and in聽vivo with excellent potency and greatly improved selectivity, including showing no detectable cross-reactivity with FAAH. These findings designate HFIP carbamates as聽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.