Jason Clapper on “In vivo characterization of a selective monoacylglycerol lipase inhibitor ABD-1970 in rodents and activity in models of pain”

San Diego, Nov. 15, 2016


Monoacylglycerol lipase (MGLL) is the primary regulator of 2-arachidonoylglycerol (2-AG) an endogenous ligand of the cannabinoid (CB) receptors CB1 and CB2. Selective blockade of MGLL inhibits the hydrolytic degradation of 2-AG resulting in elevated 2-AG levels in the CNS and periphery, and CB1/2-dependent anti-nociceptive and anti-inflammatory effects. In the rodent brain and select peripheral tissues, MGLL inactivation also reduces levels of the catabolic product of 2-AG hydrolysis, arachidonic acid, a metabolic precursor to pro-inflammatory prostanoids. Here, we present a comprehensive in vivo characterization of a selective covalent inhibitor of MGLL, ABD-1970. ABD-1970 is orally active in rodents producing a rapid and potent inhibition of MGLL and elevation of 2-AG in the brain. In vivo blockade of 2-AG hydrolysis was also associated with reduced levels of arachidonic acid and prostanoids PGE2, PGD2 and PGF2α in the brain. Using activity-based protein profiling to comprehensively profile the in vivo selectivity of ABD-1970 against other serine hydrolases, α/β-hydrolase domain-containing 6 (ABHD6) and rodent-specific carboxylesterase 1c (CES1c) were the only off-targets identified, albeit at doses above those required for in vivo pharmacological activity at MGLL. In time course experiments, MGLL activity was inversely correlated with ABD-1970 concentrations in the blood and brain with recovery of MGLL activity observed as the compound was eliminated from the body. Furthermore, ABD-1970 was efficacious in the rat incisional model of acute post-operative pain, the rat formalin and complete Freund’s adjuvant models of inflammatory pain and the rat chronic constriction injury model of neuropathic pain. In the formalin model, ABD-1970 produced enhanced activity in combination with standard of care agents, pregabalin and morphine. Integrated analysis of compound exposure, brain target engagement, and 2-AG levels reveal a strong relationship between PK, central biomarkers and efficacy in models of pain. Importantly, acute administration of ABD-1970 lacked effects on total exploratory activity in an open field test. These results identify ABD-1970 as a highly potent and selective in vivo active inhibitor of MGLL and underscore the therapeutic potential of selective MGLL inhibitors for the treatment of acute and chronic pain.

Society for Neuroscience, 2016