Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62

Reference

Title : 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)m ethanone (JJKK-048) - Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
Author(s) : Aaltonen N , Kedzierska E , Orzelska-Gorka J , Lehtonen M , Navia-Paldanius D , Jakupovic H , Savinainen JR , Nevalainen T , Laitinen JT , Parkkari T , Gynther M
Ref : Journal of Pharmacology & Experimental Therapeutics , 359 :62 , 2016
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)m ethanone (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.
ESTHER : Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
PubMedSearch : Aaltonen_2016_J.Pharmacol.Exp.Ther_359_62
PubMedID: 27451409

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Aaltonen N, Kedzierska E, Orzelska-Gorka J, Lehtonen M, Navia-Paldanius D, Jakupovic H, Savinainen JR, Nevalainen T, Laitinen JT, Parkkari T, Gynther M (2016)
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)m ethanone (JJKK-048)
Journal of Pharmacology & Experimental Therapeutics 359 :62

Aaltonen N, Kedzierska E, Orzelska-Gorka J, Lehtonen M, Navia-Paldanius D, Jakupovic H, Savinainen JR, Nevalainen T, Laitinen JT, Parkkari T, Gynther M (2016)
Journal of Pharmacology & Experimental Therapeutics 359 :62