Dual Fatty Acid Amide Hydrolase (FAAH)/Monoacylglycerol lipase (MAGL) Inhibitors for Cannabis Use Disorder (CUD). - OTHER PROJECT INFORMATION – Unit 7 – Project Summary/Abstract This project addresses the growing need for medications for cannabis use disorder (CUD) which, in the absence of approved medications, is a major focus of NIDA’s mission. Currently available cannabinergic-based treatments for CUD include the directly acting CB1 agonists, e.g., Δ9-THC or nabilone, which have been reported to reduce cannabis withdrawal symptoms in humans supporting the therapeutic utility of agonist-based medications for management of CUD. However, the use of directly acting CB1 receptor agonists is complicated by adverse cannabimimetic effects, including erratic pharmacokinetics, unwanted physiological and subjective effects that overlap with those of smoked marijuana, and considerable dependence liability. An alternate avenue for developing agonist-based treatments for CUD may lie in drugs that indirectly enhance cannabinergic activity, e.g., by inhibiting the metabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) to increase brain levels of the endocannabinoids N-arachidonoylethanolamine (anandamide, AEA) or 2-arachidonylglycerol (2-AG), respectively. This view is strengthened by our preliminary findings from CB1-discrimination studies in monkeys showing that combined inhibition of FAAH and MAGL, but neither action alone, can produce Δ9-THC-like interoceptive effects. More recently, we identified a second-generation dual FAAH-MAGL inhibitor MAK2376 with improved druggability profile compared to the parent dual FAAH-MAGL inhibitor AM4302, i.e., MAK2376 showed greater stability to hepatic microsomes and higher aqueous solubility relative to AM4302. Encouraged by these findings, we plan to optimize pharmacokinetic and pharmacological parameters of MAK2376 by designing, synthesizing, and evaluating novel derivatives in vitro and in vivo assays. Novel high potency ligands will be tested in microsomal stability, aqueous solubility, and pharmacokinetic assays. Criteria for selecting ligands for in vivo studies include: IC50<10 nM (r/hFAAH), <500 nM (r/hMAGL); varying rFAAH/rMAGL inhibition ratio, (e.g.,1/10, 1/50, 1/100); CB1: Ki >300 nM; microsomal stability, t1/2 (minutes) >15 (m, r) and >30 (human); aqueous solubility (pH 7.4) >60 ug/m; oral bioavailability >25% and brain/plasma ratio >50%. Select compounds will be tested in vivo tetrad and CB1 discrimination assays in rats. Our overarching goal will be to discover improved mixed-action FAAH-MAGL inhibitors that produce Δ9-THC-like stimulus effects at doses that produce minimal CB1-associated tetrad side-effects (e.g., hypothermia/catalepsy). The most promising 2-4 ligands will be advanced to Phase II studies in nonhuman primates for further optimization. We anticipate that novel mixed-action FAAH-MAGL inhibitors that are successful in this Phase I and highly translational Phase II studies in nonhuman primates will be ‘lead’ compounds that will be further studied in preclinical and clinical trials as candidate medications for CUD. Our multidisciplinary team of scientific and business experts is well suited to successfully advance this project to commercialization phase II.
