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

Chem Biol. 2012 May 25;19(5):579-88. doi: 10.1016/j.chembiol.2012.03.009. Epub 2012 Apr 26.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amidohydrolases / metabolism
  • Animals
  • Arachidonic Acids / metabolism
  • Cannabinoid Receptor Modulators / metabolism*
  • Carbamates / chemistry*
  • Carbamates / pharmacology*
  • Endocannabinoids*
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Glycerides / metabolism
  • HEK293 Cells
  • Humans
  • Mice
  • Mice, Inbred C57BL
  • Models, Molecular
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Monoacylglycerol Lipases / metabolism
  • Rats
  • Rats, Wistar

Substances

  • Arachidonic Acids
  • Cannabinoid Receptor Modulators
  • Carbamates
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases
  • Amidohydrolases
  • fatty-acid amide hydrolase
  • anandamide