Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl
Supplemental material to this article can be found at: http://jpet.aspetjournals.org/content/suppl/2019/12/09/jpet.119.262139.DC1 1521-0103/372/3/339–353$35.00 https://doi.org/10.1124/jpet.119.262139 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 372:339–353, March 2020 Copyright ª 2020 by The American Society for Pharmacology and Experimental Therapeutics Pharmacologic Characterization of JNJ-42226314, [1-(4-Fluorophenyl)indol-5-yl]-[3-[4-(thiazole-2-carbonyl) piperazin-1-yl]azetidin-1-yl]methanone, a Reversible, Selective, and Potent Monoacylglycerol Lipase Inhibitor s Ryan M. Wyatt, Ian Fraser, Natalie Welty, Brian Lord, Michelle Wennerholm, Steven Sutton, Michael K. Ameriks, Christine Dugovic, Sujin Yun, Allison White, Leslie Nguyen, Tatiana Koudriakova, Gaochao Tian, Javier Suarez, Lawrence Szewczuk, William Bonnette, Kay Ahn, Brahma Ghosh, Christopher M. Flores, Peter J. Connolly, Downloaded from Bin Zhu, Mark J. Macielag, Michael R. Brandt, Kristen Chevalier, Sui-Po Zhang, Timothy Lovenberg, and Pascal Bonaventure Janssen Research & Development, LLC, San Diego, California Received August 16, 2019; accepted December 1, 2019 jpet.aspetjournals.org ABSTRACT The serine hydrolase monoacylglycerol lipase (MAGL) is the rate- respectively. Though 30 mg/kg induced hippocampal synaptic limiting enzyme responsible for the degradation of the endo- depression, altered sleep onset, and decreased electroencephalo- cannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid gram gamma power, 3 mg/kg still provided approximately 80% en- and glycerol. Inhibition of 2-AG degradation leads to elevation of zyme occupancy, significantly increased 2-AG and norepinephrine 2-AG, the most abundant endogenous agonist of the cannabi- levels, and produced neuropathic antinociception without synaptic at ASPET Journals on September 24, 2021 noid receptors (CBs) CB1 and CB2.
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