RT Journal Article
SR Electronic
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
FD American Society for Pharmacology and Experimental Therapeutics
SP jpet.118.252296
DO 10.1124/jpet.118.252296
A1 Jason R Clapper
A1 Cassandra L Henry
A1 Micah J Niphakis
A1 Anna M Knize
A1 Aundrea R Coppola
A1 Gabriel M Simon
A1 Nhi Ngo
A1 Rachel A Herbst
A1 Dylan M Herbst
A1 Alex W Reed
A1 Justin S Cisar
A1 Olivia D Weber
A1 Andreu Viader
A1 Jessica P Alexander
A1 Mark L Cunningham
A1 Todd K Jones
A1 Iain P Fraser
A1 Cheryl A Grice
A1 R. Alan B. Ezekowitz
A1 Gary P O'Neill
A1 Jacqueline L Blankman
YR 2018
UL http://jpet.aspetjournals.org/content/early/2018/10/10/jpet.118.252296.abstract
AB 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 neurological 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. As MGLL contributes to arachidonic acid (AA) 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 (COX) inhibitors. ABD-1970 robustly elevated brain 2-AG content and displayed antinociceptive and anti-pruritic 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 neurological disorders.