In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048)

J Pharmacol Exp Ther. 2016 Oct;359(1):62-72. doi: 10.1124/jpet.116.233114. Epub 2016 Jul 22.

Abstract

Monoacylglycerol lipase (MAGL) is a serine hydrolase that acts as a principal degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). In addition to terminating the signaling function of 2-AG, MAGL liberates arachidonic acid to be used as a primary source for neuroinflammatory prostaglandin synthesis in the brain. MAGL activity also contributes to cancer pathogenicity by producing precursors for tumor-promoting bioactive lipids. Pharmacological inhibitors of MAGL provide valuable tools for characterization of MAGL and 2-AG signaling pathways. They also hold great therapeutic potential to treat several pathophysiological conditions, such as pain, neurodegenerative disorders, and cancer. We have previously reported piperidine triazole urea, {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1H-1,2,4-triazol-1-yl)methanone (JJKK-048), to be an ultrapotent and highly selective inhibitor of MAGL in vitro. Here, we characterize in vivo effects of JJKK-048. Acute in vivo administration of JJKK-048 induced a massive increase in mouse brain 2-AG levels without affecting brain anandamide levels. JJKK-048 appeared to be extremely potent in vivo. Activity-based protein profiling revealed that JJKK-048 maintains good selectivity toward MAGL over other serine hydrolases. Our results are also the first to show that JJKK-048 promoted significant analgesia in a writhing test with a low dose that did not cause cannabimimetic side effects. At a high dose, JJKK-048 induced analgesia both in the writhing test and in the tail-immersion test, as well as hypomotility and hyperthermia, but not catalepsy.

MeSH terms

  • Animals
  • Arachidonic Acids / metabolism
  • Behavior, Animal / drug effects
  • Benzodioxoles / adverse effects
  • Benzodioxoles / pharmacokinetics
  • Benzodioxoles / pharmacology*
  • Brain / drug effects
  • Brain / metabolism
  • Dose-Response Relationship, Drug
  • Endocannabinoids / metabolism
  • Enzyme Inhibitors / adverse effects
  • Enzyme Inhibitors / pharmacokinetics
  • Enzyme Inhibitors / pharmacology*
  • Glycerides / metabolism
  • Hypothermia / chemically induced
  • Male
  • Mice
  • Monoacylglycerol Lipases / antagonists & inhibitors*
  • Nociception / drug effects
  • Piperidines / adverse effects
  • Piperidines / pharmacokinetics
  • Piperidines / pharmacology*
  • Pyrazoles / pharmacology
  • Rimonabant

Substances

  • Arachidonic Acids
  • Benzodioxoles
  • Endocannabinoids
  • Enzyme Inhibitors
  • Glycerides
  • JJNK-048
  • Piperidines
  • Pyrazoles
  • glyceryl 2-arachidonate
  • Monoacylglycerol Lipases
  • Rimonabant