TY - JOUR T1 - Monoacylglycerol Lipase Inhibition in Human and Rodent Systems Supports Clinical Evaluation of Endocannabinoid Modulators JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 494 LP - 508 DO - 10.1124/jpet.118.252296 VL - 367 IS - 3 AU - Jason R. Clapper AU - Cassandra L. Henry AU - Micah J. Niphakis AU - Anna M. Knize AU - Aundrea R. Coppola AU - Gabriel M. Simon AU - Nhi Ngo AU - Rachel A. Herbst AU - Dylan M. Herbst AU - Alex W. Reed AU - Justin S. Cisar AU - Olivia D. Weber AU - Andreu Viader AU - Jessica P. Alexander AU - Mark L. Cunningham AU - Todd K. Jones AU - Iain P. Fraser AU - Cheryl A. Grice AU - R. Alan B. Ezekowitz AU - Gary P. O’Neill AU - Jacqueline L. Blankman Y1 - 2018/12/01 UR - http://jpet.aspetjournals.org/content/367/3/494.abstract N2 - Monoacylglycerol lipase (MGLL) is the primary degradative enzyme for the endocannabinoid 2-arachidonoylglycerol (2-AG). The first MGLL inhibitors have recently entered clinical development for the treatment of neurologic disorders. To support this clinical path, we report the pharmacological characterization of the highly potent and selective MGLL inhibitor ABD-1970 [1,1,1,3,3,3-hexafluoropropan-2-yl 4-(2-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-4-chlorobenzyl)piperazine-1-carboxylate]. We used ABD-1970 to confirm the role of MGLL in human systems and to define the relationship between MGLL target engagement, brain 2-AG concentrations, and efficacy. Because MGLL contributes to arachidonic acid metabolism in a subset of rodent tissues, we further used ABD-1970 to evaluate whether selective MGLL inhibition would affect prostanoid production in several human assays known to be sensitive to cyclooxygenase inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and antipruritic activity in a battery of rodent models (ED50 values of 1–2 mg/kg). The antinociceptive effects of ABD-1970 were potentiated when combined with analgesic standards of care and occurred without overt cannabimimetic effects. ABD-1970 also blocked 2-AG hydrolysis in human brain tissue and elevated 2-AG content in human blood without affecting stimulated prostanoid production. These findings support the clinical development of MGLL inhibitors as a differentiated mechanism to treat pain and other neurologic disorders. ER -