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)methanone (JJKK-048).
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.
authors.affiliation: 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.) Aaltonen@uef.fi.
authors.forename: Niina
authors.initials: N
authors.lastname: Aaltonen
authors.affiliation: 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.).
authors.forename: Ewa
authors.initials: E
authors.lastname: Kedzierska
authors.affiliation: 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.).
authors.forename: Jolanta
authors.initials: J
authors.lastname: Orzelska-Górka
authors.affiliation: 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.).
authors.forename: Marko
authors.initials: M
authors.lastname: Lehtonen
authors.affiliation: 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.).
authors.forename: Dina
authors.initials: D
authors.lastname: Navia-Paldanius
authors.affiliation: 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.).
authors.forename: Hermina
authors.initials: H
authors.lastname: Jakupovic
authors.affiliation: 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.).
authors.forename: Juha R
authors.initials: JR
authors.lastname: Savinainen
authors.affiliation: 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.).
authors.forename: Tapio
authors.initials: T
authors.lastname: Nevalainen
authors.affiliation: 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.).
authors.forename: Jarmo T
authors.initials: JT
authors.lastname: Laitinen
authors.affiliation: 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.).
authors.forename: Teija
authors.initials: T
authors.lastname: Parkkari
authors.affiliation: 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.).
authors.forename: Mikko
authors.initials: M
authors.lastname: Gynther
mesh_terms: D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D052117:Benzodioxoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D005989:Glycerides / Q000378:metabolism; D007035:Hypothermia / Q000139:chemically induced; D008297:Male; D051379:Mice; D008994:Monoacylglycerol Lipases / Q000037:antagonists & inhibitors*; D059225:Nociception / Q000187:drug effects; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology; D000077285:Rimonabant
chemical_list: D001095:Arachidonic Acids; D052117:Benzodioxoles; D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D005989:Glycerides; C000619376:JJNK-048; D010880:Piperidines; D011720:Pyrazoles; C094503:glyceryl 2-arachidonate; D008994:Monoacylglycerol Lipases; D000077285:Rimonabant