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).

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 primary source for neuroinflammatory prostaglandin synthesis in brain. MAGL activity also contributes in 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 as well as 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 (ABPP) revealed that JJKK-048 maintains good selectivity towards MAGL over other serine hydrolases. Our results also showed for the first time that JJKK-048 promoted significant analgesia in writhing test with the low dose that did not cause cannabimimetic side effects. A high dose of JJKK-048 induced analgesia both in writhing test and in tail immersion test, as well as hypomotility and hypothermia but not catalepsy.
The American Society for Pharmacology and Experimental Therapeutics.