Monoacylglycerol Lipase Inhibitors for Treating Opioid Use Disorders

描述（由申请人提供）：长期使用处方止痛剂和非法药物引起的阿片类药物成瘾是一个未得到解决的重大公共卫生危机。目前针对阿片类药物依赖的药物疗法，如阿片类药物维持疗法（如美沙酮和丁丙诺啡），减少了对非法物质的需求，减轻了阿片类药物的戒断，但与其他阿片类药物具有相似的副作用，也可能引发严重的阿片类药物戒断反应。因此，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少阿片类药物依赖动物的纳洛酮沉淀戒断症状。然而，四氢大麻酚和其他CB1受体激动剂显示出一些类似大麻的副作用，包括类似大麻的主观活动，这限制了它们的一般治疗潜力。另外，通过阻断其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），增加内源性大麻素anandamide和2-花生四烯酰基甘油（2-AG）的脑水平是一种有希望的治疗方法，缺乏直接作用CB1受体激动剂的许多不良副作用。我们最近开发了JZL184，这是第一种高效、选择性、口服活性的MAGL抑制剂。该化合物可显著提高吗啡依赖小鼠脑2-AG水平，并显著降低纳洛酮诱发的躯体戒断反应的强度，但与四氢大麻酚相比，其诱导的大麻模拟效应要小得多。虽然FAAH抑制剂对疼痛和焦虑的临床前模型有显著影响，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功效。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戒瘾恒河猴的戒断症状。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阿片类药物依赖的啮齿动物和非人灵长类动物戒断症状方面的代谢、药代动力学、靶标选择性、安全性和有效性。以下三个主要假设将被验证：1)MAGL抑制剂将减少阿片类药物依赖啮齿动物的躯体和情感戒断症状；2) MAGL抑制剂可减轻阿片类药物依赖恒河猴的阿片类药物戒断症状和戒断相关的海洛因自我给药增加；3)与直接的阿片和大麻素受体激动剂相比，抑制MAGL的副作用最小。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，在小鼠和猴子的临床前模型中防止阿片类药物戒断，并为ind的毒理学研究做好准备，作为一种治疗阿片类药物滥用的新疗法进入临床开发。

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. PUBLIC HEALTH RELEVANCE: Opioid addicts undergoing abstinence suffer from a constellation of physiological and behavioral withdrawal signs that cause great suffering and high-potential for relapse to drug usage; new targeted therapies are desperately needed to assist addicts in alleviating their dependence on opioid drugs while minimizing the potential for relapse. Here, we propose an innovative new way to treat opioid withdrawal with selective inhibitors of the endocannabinoid-degrading enzyme monoacylglycerol lipase (MAGL) and detail a plan to test this premise by developing best-in-class MAGL inhibitors with good translational potential for evaluation in animal models of opioid dependence and withdrawal. If successful, this research program could deliver next- generation therapies for opioid addiction that show excellent efficacy with limited potential for side effects and drug relapse.