Dual Fatty Acid Amide Hydrolase (FAAH)/Monoacylglycerol lipase (MAGL) Inhibitors for Cannabis Use Disorder (CUD).

其他项目信息-第7单元-项目概要/摘要 该项目解决了对大麻使用障碍药物日益增长的需求， 没有批准的药物，是NIDA使命的主要焦点。目前可用的基于大麻素的 CUD的治疗包括直接作用的CB 1激动剂，例如，Δ9-THC或那比隆，它们已经被 据报道，减少人类大麻戒断症状，支持基于激动剂的 治疗CUD的药物。然而，直接作用的CB 1受体激动剂的使用是复杂的 不良的拟大麻作用，包括不稳定的药代动力学，不必要的生理和主观的 与吸食大麻重叠的影响，以及相当大的依赖性。一个替代 开发基于激动剂的CUD治疗方法的途径可能在于间接增强大麻能的药物， 活动，例如，通过抑制代谢酶脂肪酸酰胺水解酶（FAAH）和单酰基甘油 脂肪酶（MAGL）以增加内源性大麻素N-花生四烯酰乙醇胺（花生四烯酰胺， AEA）或2-花生四烯酸甘油（2-AG）。我们的初步调查结果加强了这一观点， 在猴子中进行的CB 1-辨别研究表明，FAAH和MAGL的联合抑制作用， 单独使用，可产生Δ9-THC样内感受效应。最近，我们发现了第二代双 与母体双重FAAH-MAGL相比，FAAH-MAGL抑制剂MAK 2376具有改善的可药用性特征 抑制剂AM4302，即，MAK 2376对肝微粒体的稳定性更高，水溶性更高 关于AM4302受这些发现的鼓舞，我们计划优化药代动力学和药理学 MAK 2376的参数，通过设计，合成和评价新的衍生物在体外和体内 测定。新型高效配体将在微粒体稳定性、水溶性和生物相容性方面进行测试。 药代动力学测定。选择用于体内研究的配体的标准包括：IC 50 <10 nM（r/hFAAH），<500 nM（r/hFAAH）， nM（r/hMAGL）;不同的rFAAH/rMAGL抑制比（例如，1/10，1/50，1/100）; CB 1：Ki >300 nM;微粒体 稳定性，t1/2（分钟）>15（m，r）和>30（人）;水溶性（pH 7.4）>60 ug/m;口服生物利用度 >25%和脑/血浆比> 50%。选择化合物将在体内四分体和CB 1辨别中进行测试 在大鼠中的测定。我们的首要目标将是发现改进的混合作用FAAH-MAGL抑制剂， 在产生最小CB 1相关四分体副作用的剂量下产生Δ9-THC样刺激作用（例如， 体温过低/僵住症）。最有前途的2-4配体将进入非人类的II期研究。 灵长类动物进行进一步优化。我们预计，新的混合作用FAAH-MAGL抑制剂， 在非人灵长类动物中成功进行的I期和高度转化的II期研究将是“领先的” 这些化合物将作为CUD的候选药物在临床前和临床试验中进一步研究。我们 由科学和商业专家组成的多学科团队非常适合成功推进该项目， 商业化阶段二。

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.