PT  - JOURNAL ARTICLE
AU  - Niina Aaltonen
AU  - Ewa Kedzierska
AU  - Jolanta Orzelska-Górka
AU  - Marko Lehtonen
AU  - Dina Navia-Paldanius
AU  - Hermina Jakupovic
AU  - Juha R. Savinainen
AU  - Tapio Nevalainen
AU  - Jarmo T. Laitinen
AU  - Teija Parkkari
AU  - Mikko Gynther
TI  - In Vivo Characterization of the Ultrapotent Monoacylglycerol Lipase Inhibitor {4-[bis-(benzo[d][1,3]dioxol-5-yl)methyl]-piperidin-1-yl}(1<em>H</em>-1,2,4-triazol-1-yl)methanone (JJKK-048)
AID  - 10.1124/jpet.116.233114
DP  - 2016 Oct 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 62--72
VI  - 359
IP  - 1
4099  - http://jpet.aspetjournals.org/content/359/1/62.short
4100  - http://jpet.aspetjournals.org/content/359/1/62.full
SO  - J Pharmacol Exp Ther2016 Oct 01; 359
AB  - 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.