Monoacylglycerol Lipase Inhibitors for Treating Opioid Use Disorders

描述(由申请人提供)：长期使用处方镇痛剂和非法药物造成的阿片成瘾是一个重大的未得到满足的公共卫生危机。目前治疗阿片依赖的药物疗法，如阿片维持疗法(如美沙酮和丁丙诺啡)，可减少对非法物质的需求，缓解阿片戒断，但具有与其他阿片相似的副作用，也可引发严重的阿片戒断反应。因此，仍然迫切需要开发新的治疗策略，以减轻患者对阿片类药物的依赖，而不会将这种依赖转移到另一种药物上。D9-四氢大麻酚(THC)是大麻中的主要精神活性成分，长期以来一直被认为可以减轻阿片依赖动物的纳洛酮催促戒断症状。然而，THC和其他CB1受体激动剂表现出几种类似大麻的副作用，包括大麻样的主观活动，限制了它们的一般治疗潜力。或者，通过阻断内源性大麻素胺和2-花生四烯基甘油(2-AG)各自的分解代谢酶脂肪酸酰胺水解酶(FAAH)和单酰基甘油脂肪酶(MAGL)来增加大脑中的水平，是一种有希望的治疗方法，它没有许多直接作用的CB1受体激动剂的不良副作用。我们最近开发了第一个高效、选择性和口服活性的MAGL抑制剂JZL184。该化合物可显著提高脑内2-AG水平，并显著降低吗啡依赖小鼠纳洛酮催促的躯体戒断反应的幅度，但与THC相比，产生的拟大麻效应要小得多。虽然FAAH抑制剂在疼痛和焦虑的临床前模型中产生了显著的效果，但我们的初步数据显示，这些化合物在减少阿片类药物戒断效应方面缺乏有效性。因此，这项建议的总体目标是测试优化的MAGL抑制剂是否将减少阿片依赖小鼠和经历戒断的恒河猴的戒断症状。在拟议的实验中，我们将表征JZL184及其结构相关类似物在改善已建立的阿片类药物依赖的啮齿动物和非人类灵长类动物模型中的戒断症状方面的代谢、药代动力学、靶向选择性、安全性和有效性。将检验以下三个主要假设：1)MAGL抑制剂将减少阿片依赖啮齿动物的躯体和情感戒断症状；2)MAGL抑制剂将减少阿片依赖猕猴的阿片戒断症状和与戒断相关的海洛因自我给药增加；以及3)与直接阿片和大麻受体激动剂相比，抑制MAGL产生的副作用最小。该应用的最终目标是确定一种有效的、选择性的、口服活性的、安全和有效的MAGL抑制剂，它可以在小鼠和猴子的临床前模型中防止阿片类药物的戒断，并准备作为一种治疗阿片类药物滥用的新疗法在临床开发过程中启用IND毒理学。

DESCRIPTION (provided by applicant): Opioid addiction from the chronic use of prescription analgesics and illicit agents represents a major unmet public health crisis. Current pharmacotherapies for opioid dependence, such as opioid maintenance therapy (e.g., methadone and buprenorphine), reduce the need for illicit substances and alleviate opioid withdrawal, but possess a similar side effect profile as other opioids and can also trigger severe opioid withdrawal responses. Consequently, a strong need remains for the development of new treatment strategies that would relieve patients of opioid dependence without transferring this dependency to another drug. D9-tetrahydrocannabinol (THC), the primary psychoactive constituent in Cannabis sativa, has long been known to reduce naloxone- precipitated withdrawal symptoms in opioid-dependent animals. However, THC and other CB1 receptor agonists display several cannabimimetic side effects, including marijuana-like subjective activity, that limit their general therapeutic potential. Alternatively, increasing brain levels of the endogenous cannabinoids anandamide and 2-arachidonylglycerol (2-AG) though the blockade of their respective catabolic enzymes fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) represents a promising therapeutic approach that lacks many of the undesirable side effects of direct-acting CB1 receptor agonists. We have recently developed JZL184, the first highly potent, selective, and orally active MAGL inhibitor. This compound causes significant elevations in brain 2-AG levels and robustly reduces the magnitude of naloxone-precipitated somatic withdrawal responses in morphine-dependent mice, but elicits far fewer cannabimimetic effects compared with THC. While FAAH inhibitors produce significant effects in preclinical models of pain and anxiety, our preliminary data show that these compounds lack efficacy in reducing opioid withdrawal effects. Thus, the overall objective of this proposal is to test whether optimized MAGL inhibitors will reduce the constellation of withdrawal symptoms in opioid-dependent mice and rhesus monkeys undergoing abstinence. In the proposed experiments, we will characterize the metabolism, pharmacokinetics, target selectivity, safety profile, and effectiveness of JZL184 and structurally related analogues in ameliorating withdrawal symptoms in established rodent and nonhuman primate models of opioid dependence. The following three major hypotheses will be tested: 1) MAGL inhibitors will reduce somatic and affective withdrawal signs in opioid- dependent rodents; 2) MAGL inhibitors will reduce opioid withdrawal symptoms and withdrawal-related increases in heroin self-administration in opioid-dependent rhesus monkeys; and 3) inhibition of MAGL will produce minimal side effects compared to direct opioid and cannabinoid receptor agonists. The ultimate goal of this application is to identify a potent, selective, orally active, safe, and efficacious MAGL inhibitor that prevents opioid withdrawal in mouse and monkey preclinical models and is ready for IND-enabling toxicology en route to clinical development as a novel therapeutic for treating opioid abuse.