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 NIDAs mission. Currently available cannabinergic-based treatments for CUD include the directly acting CB1 agonists, e.g., ?9-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 ?9-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 ?9-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.
Public Health Relevance Statement
OTHER PROJECT INFORMATION Unit 8 - Project Narrative Dual Fatty Acid Amide Hydrolase (FAAH)/Monoacylglycerol Lipase (MAGL) Inhibitors for Cannabis Use Disorder (CUD). Recent widespread use of marijuana or other cannabis products for medical and recreational purposes has contributed to increasing incidences of cannabis use disorder (CUD) that represents a major threat to public health. Currently, no FDA-approved medications are available for treating CUD, which points to a pressing need for developing new effective candidate medications. This project will address this concern with research to develop and identify novel medications that indirectly enhance cannabinergic activity by concurrently inhibiting enzymes that breakdown endocannabinoids, thereby, increasing their levels in the brain to counter CUD.
Project Terms: Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Brain; Brain Nervous System; Encephalon; Catalepsy; Anochlesia; Clinical Trials; Discrimination; Cognitive Discrimination; Drug Design; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Enzymes; Enzyme Gene; Exhibits; Goals; Government; Human; Modern Man; natural hypothermia; Hypothermia; In Vitro; Incidence; Isoenzymes; Isozymes; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Marijuana; marihuana; Microsomes; Mission; Monkeys; Monoacylglycerol Lipases; Glycerol Monoester Hydrolases; Glycerol-ester acylhydrolase; Monoglyceride Esterases; Monoglyceride Hydrolase; Monoglyceride Lipases; Persons; Parents; parent; Drug Kinetics; Pharmacokinetics; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Public Health; Rattus; Common Rat Strains; Rat; Rats Mammals; Recreation; Research; Rodent; Rodentia; Rodents Mammals; Science; Self Administration; Self Administered; Smoke; Solubility; Testing; Time; Universities; Work; Nabilone; Cesamet; Generations; Businesses; Mediating; Withdrawal Symptom; Analgesic Management; Pharmacologic Management; medication therapy management; Medication Management; improved; Hepatic; Phase; Physiologic; Physiological; Biochemical; Medical; N arachidonoyl 2 hydroxyethylamide; N-arachidonoylethanolamine; arachidonoyl ethanolamide; arachidonoylethanolamide; arachidonylethanolamide; anandamide; Evaluation; Stimulus; non-human primate; nonhuman primate; Withdrawal; Selection Criteria; Agonist; Phase 2 Clinical Trials; phase II protocol; Phase II Clinical Trials; 2-AG; 2-arachidonoyl-glycerol; 2-arachidonoyl-sn-glycerol; 2-arachidonoylglycerol; 2-arachidonyl-glycerol; 2-arachidonylglycerol; Therapeutic; Metabolic; ABCB1 gene; ABC20; ABCB1; GP170; MDR-1; MDR1; MDR1 Protein; Multidrug Resistance 1; Multidrug Resistance Gene-1; Multidrug Resistance Gene-1s; Multidrug Resistance Proteins; Multidrug Resistant Proteins; P-GP; P-Glycoprotein; P-Glycoprotein 1 Gene; PGY-1 Protein; PGY1; CNR1 gene; CB1; CB1 Receptor; CB1R; Cannabinoid Receptor CB1; cannabinoid receptor 1; cannabinoid receptor type 1; cannabinoid type 1; Dependence; Oral; fatty acid amide hydrolase; FAAH protein; oleamide hydrolase; professor; aqueous; drug discrimination; novel; Exclusion; Reporting; Property; response; drug development; drug discovery; drug synthesis; Drug Synthesis and Chemistry; Cannabis; Endogenous Cannabinoids; Endocannabinoids; Pharmaceutical Agent; Pharmaceuticals; Pharmacological Substance; pharmaceutical; Pharmacologic Substance; cheminformatics; chemical informatics; Address; Dose; Symptoms; Affinity; National Institute of Drug Abuse; NIDA; National Institute on Drug Abuse; in vivo; Enzyme Inhibition; Development; developmental; Behavioral; Behavioral Assay; designing; design; scale up; Abstinence; multidisciplinary; clinical applicability; clinical application; commercialization; eCB system; endocannabinoid system; endogenous cannabinoid system; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; FDA approved; phase II study; phase 2 study; cannabimimetics; cannabis use disorder; marijuana use and disorder; marijuana use disorder; behavior study; behavioral study; cannabis withdrawal; THC co-use; THC use; Tetrahydrocannabinol co-use; Tetrahydrocannabinol use; cannabis use; marijuana use; pre-clinical trial; preclinical trial; monoacylglycerol lipase inhibitor; MAGL inhibitor; in vivo testing; in vivo evaluation; side effect; pharmacologic; cannabinergic; cannabinoidergic
