RT Journal Article SR Electronic T1 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 JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP jpet.119.262139 DO 10.1124/jpet.119.262139 A1 Ryan M Wyatt A1 Ian Fraser A1 Natalie Welty A1 Brian Lord A1 Michelle Wennerholm A1 Steven W Sutton A1 Michael K Ameriks A1 Christine Dugovic A1 Sujin Yun A1 Allison White A1 Leslie Nguyen A1 Tatiana Koudriakova A1 Gaochao Tian A1 Javier Suarez A1 Lawrence Szewczuk A1 William Bonnette A1 Kay Ahn A1 Brahma Ghosh A1 Christopher M Flores A1 Peter J Connolly A1 Bin Zhu A1 Mark J Macielag A1 Michael R Brandt A1 Kristen Chevalier A1 Sui-Po Zhang A1 Timothy W. Lovenberg A1 Pascal Bonaventure YR 2019 UL http://jpet.aspetjournals.org/content/early/2019/12/09/jpet.119.262139.abstract AB The serine hydrolase monoacylglycerol lipase (MAGL) is the rate-limiting enzyme responsible for the degradation of the endocannabinoid 2-arachidonoylglycerol (2-AG) into arachidonic acid and glycerol. Inhibition of 2-AG degradation leads to elevation of 2-AG, the most abundant endogenous agonist of the cannabinoid receptors CB1 and CB2. Activation of these receptors have demonstrated beneficial effects on mood, appetite, pain and inflammation. Therefore, MAGL inhibitors have the potential to produce therapeutic effects in a vast array of complex human diseases. The present report describes the 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 and highly selective MAGL inhibitor. JNJ-42226314 inhibits MAGL in a competitive mode with respect to the 2-AG substrate. In rodent brain, the compound time- and dose-dependently bound to MAGL, indirectly led to CB1 occupancy by raising 2-AG levels and raised norepinephrine levels in cortex. In vivo, the compound exhibited antinociceptive efficacy in both the rat complete Freund's adjuvant (CFA)-induced radiant heat hypersensitivity and chronic constriction injury (CCI)-induced cold hypersensitivity models of inflammatory and neuropathic pain, respectively. Although 30 mg/kg induced hippocampal synaptic depression, altered sleep onset and decreased EEG gamma power, 3 mg/kg still provided approximately 80% enzyme occupancy, significantly increased 2-AG and norepinephrine levels and produced neuropathic antinociception without synaptic depression or decreased gamma power. Thus, it is anticipated that the profile exhibited by this compound will allow for precise modulation of 2-AG levels in vivo, supporting potential therapeutic application in several CNS disorders.SIGNIFICANCE STATEMENT Potentiation of endocannabinoid signaling activity via inhibition of the serine hydrolase monoacylglycerol lipase (MAGL) is an appealing strategy in the development of treatments for several disorders, including ones related to mood, pain and inflammation. JNJ-42226314 is presented in this report to be a novel, potent, selective and reversible non-covalent MAGL inhibitor that demonstrates dose-dependent enhancement of the major endocannabinoid 2-arachidonoylglycerol as well as efficacy in models of neuropathic and inflammatory pain.