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.
Niina Aaltonen  1 ,  Ewa Kedzierska  2 ,  Jolanta Orzelska-Górka  2 ,  Marko Lehtonen  2 ,  Dina Navia-Paldanius  2 ,  Hermina Jakupovic  2 ,  Juha R Savinainen  2 ,  Tapio Nevalainen  2 ,  Jarmo T Laitinen  2 ,  Teija Parkkari  2 ,  Mikko Gynther  2
Affiliations
  • 1. School of Medicine, Institute of Biomedicine/Physiology (N.A., D.N.-P., H.J., J.R.S., J.T.L.), and School of Pharmacy, (M.L., T.N., T.P., M.G.), University of Eastern Finland, Kuopio, Finland; and Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, Lublin, Poland (E.K., J.O.-G.) [email protected].
  • 2. School of Medicine, Institute of Biomedicine/Physiology (N.A., D.N.-P., H.J., J.R.S., J.T.L.), and School of Pharmacy, (M.L., T.N., T.P., M.G.), University of Eastern Finland, Kuopio, Finland; and Department of Pharmacology and Pharmacodynamics, Faculty of Pharmacy with Division of Medical Analytics, Medical University of Lublin, Lublin, Poland (E.K., J.O.-G.).
PMID: 27451409 DOI: 10.1124/jpet.116.233114
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.

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