Abstract
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.
Highlights
Monoacylglycerol lipase (MGLL; known as MAG lipase, MAGL, and MGL) is a serine hydrolase enzyme that regulates the endocannabinoid and eicosanoid families of lipid signaling molecules (Grabner et al, 2017)
In vitro treatment of tissue or cell homogenates with ABD1970, followed by incubation with activity-based protein profiling (ABPP) probes, SDS-PAGE analysis, and in-gel fluorescence imaging, allows for the direct visualization of the targets of ABD-1970. In this gel-based ABPP platform, quantification of serine hydrolase activity is based on the intensity of probe labeling, and inhibition is measured as a reduction of probe labeling compared with control samples
human prostate carcinoma (PC3) cells are a rich source of human MGLL, as well as of a/b hydrolase domain containing 6 (ABHD6), an off-target common to published MGLL inhibitors (Long et al, 2009a; Chang et al, 2012; Niphakis et al, 2012; Griebel et al, 2015; Butler et al, 2017)
Summary
Monoacylglycerol lipase (MGLL; known as MAG lipase, MAGL, and MGL) is a serine hydrolase enzyme that regulates the endocannabinoid and eicosanoid families of lipid signaling molecules (Grabner et al, 2017). Parts of this work were previously presented in poster form at the following meeting: Clapper JR, Blankman JL, Coppola AR, Knize A, Simon G, Cisar J, Weber O, Niphakis M, Henry C, Fraser I, et al (2016) In vivo characterization of a selective monoacylglycerol lipase inhibitor ABD-1970 in rodents and activity in models of pain (Program 617.02). Neuroscience 2016; 2016 Nov 12–16; San Diego, CA; and Blankman JL, Henry C, Knize A, Simon G, Cisar J, Weber O, Niphakis M, Clapper JR, Coppola A, Fraser I, et al (2016) In vitro characterization of a selective monoacylglycerol lipase inhibitor ABD-1970 in human systems (Program 617.03).
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