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导致的阿片类成瘾是一个重大的未解决的公共卫生危机。目前阿片类药物依赖的药物治疗，如阿片类药物维持治疗（例如，美沙酮和丁丙诺啡），减少对非法物质的需求并缓解阿片类药物戒断，但具有与其他阿片类药物相似的副作用特征，也可能引发严重的阿片类药物戒断反应。因此，仍然强烈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。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少阿片类药物依赖动物中纳洛酮诱发的戒断症状。然而，THC和其他CB 1受体激动剂显示出几种大麻模拟物的副作用，包括大麻样主观活性，这限制了它们的一般治疗潜力。或者，通过阻断内源性大麻素花生四烯酸和2-花生四烯酸甘油（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）来增加内源性大麻素花生四烯酸和2-花生四烯酸甘油（2-AG）的脑水平代表了一种有前景的治疗方法，其缺乏直接作用的CB 1受体激动剂的许多不期望的副作用。我们最近开发了JZL 184，这是第一个高效，选择性和口服活性的MAGL抑制剂。这种化合物导致大脑2-AG水平显著升高，并强烈降低吗啡依赖小鼠中纳洛酮诱发的躯体戒断反应的幅度，但与THC相比，其大麻模拟作用要少得多。虽然FAAH抑制剂在疼痛和焦虑的临床前模型中产生显著效果，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作用方面缺乏疗效。因此，本提案的总体目标是测试优化的MAGL抑制剂是否会减少阿片类药物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，我们将表征代谢，药代动力学，目标选择性，安全性和有效性JZL 184和结构相关的类似物在改善戒断症状，在已建立的啮齿动物和非人灵长类动物模型阿片类药物依赖。将测试以下三个主要假设：1）MAGL抑制剂将减少阿片类药物依赖性啮齿动物中的躯体和情感戒断体征; 2）MAGL抑制剂将减少阿片类药物依赖性恒河猴中阿片类药物戒断症状和海洛因自我给药的戒断相关增加;和3）与直接阿片类药物和大麻素受体激动剂相比，MAGL的抑制将产生最小的副作用。本申请的最终目标是确定一种有效的、选择性的、口服活性的、安全有效的MAGL抑制剂，该抑制剂可在小鼠和猴临床前模型中预防阿片类药物戒断，并可作为治疗阿片类药物滥用的新型治疗药物在临床开发过程中进行IND毒理学研究。

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.