Development of selective cannabinoid receptor 2 agonists for treatment of addiction

项目摘要 美国目前面临着严重的物质使用障碍流行病。2019年，2040万美国人 12岁或以上有物质使用障碍。约有160万人患有阿片类药物使用障碍， 平均每天有超过136人因服药过量而死亡兴奋剂滥用也是一个重要因素 这场社会危机的范围和严重程度，有100万人患有甲基苯丙胺使用障碍（MUD） 还有一百万人因可卡因使用障碍甲基安非他明和可卡因是目前的主要原因 阿片类药物用于非法药物导致的过量死亡。美沙酮和丁丙诺啡是广泛使用的治疗方法 阿片类药物成瘾，但目前还没有批准的药物治疗兴奋剂使用障碍 （SUD）。因此，迫切需要开发SUD的药物干预措施。医用大麻 与阿片类药物处方率和死亡率降低有关，临床前研究表明， 大麻素影响成瘾性行为。这些作用被认为是由大麻素介导的 大脑中的受体。大麻素受体1和2（分别为CB 1 R和CB 2 R）是大麻素受体的一部分。 内源性大麻素系统，并在调节中枢神经系统中的多巴胺（DA）水平中起关键作用 系统（CNS）。大麻素和非选择性大麻素如THC可以激活CB 1 R和CB 2 R。 虽然已经投入了大量的努力来理解CB 1 R在该DA系统中的作用，但成瘾性神经元依赖性神经元。 大麻素的精神活性也与CB 1 R的激活有关。近期 在腹侧被盖区（VTA）DA神经元中发现抑制性CB 2受体及其抑制作用 在多巴胺能回路中，导致丘脑核（NAc）中DA释放减少，以及受体 调节中枢神经系统中的神经胶质细胞和小胶质细胞功能，为靶向该途径创造了新的机会 用于治疗发展。在过去一年U18 NIDA试点赠款的支持下，我们成功地 确定了一系列新的化学实体（NCE），这些实体对环化酶显示出功能选择性， 抑制蛋白（即，偏倚），并且对CB 2 R也具有很高的选择性，对CB 1 R具有最小的活性。我们的头号候选人 具有良好的口服吸收、脑渗透性，并且在动物模型中逆转小鼠的成瘾行为。 该提案旨在进一步优化我们的先导化合物作为临床前/临床候选治疗药物 的MUD。虽然我们的先导化合物对CB 2 R的选择性优于CB 1 R，但仍有残留的抑制蛋白， 活性，需要进一步PK优化。我们组建了一个多学科专家小组， 中枢神经系统药理学、药物化学、生物学、临床前和临床成瘾医学， 精神病学，以进一步支持这类化合物的发展与蓝图的帮助 神经治疗学网络（BPN）在人类测试之前。

Project Summary America currently faces a dire epidemic of substance use disorders. In 2019, 20.4 million Americans aged 12 or older had a substance use disorder. Approximately 1.6 million suffer from opioid use disorder, which causes more than 136 overdose deaths per day on average. Stimulant abuse is also a significant contributor to this social crisis' extension and severity, with 1 million suffering from methamphetamine use disorder (MUD) and another 1 million from cocaine use disorder. Methamphetamine and cocaine are currently major causes of overdose deaths behind opioids for illicit drugs. Methadone and buprenorphine are widely used treatments for opioid addiction, but there is currently no approved pharmacological treatment for stimulant use disorder (SUD). Thus, there is an urgent need to develop pharmacological interventions for SUD. Medical marijuana has been associated with reduced opioid prescription rates and deaths, and preclinical studies show that cannabinoids affect addictive-like behavior. These effects are believed to be mediated by cannabinoid receptors in the brain. The cannabinoid receptors 1 and 2 (CB1R and CB2R, respectively) are part of the endocannabinoid system and play a crucial role in modulating dopamine (DA) levels in the central nervous system (CNS). Marijuana and nonselective cannabinoids such as THC can activate both CB1R and CB2R. While extensive effort has been invested in understanding the role of CB1R in this DA system, the addictive and psychoactive properties of cannabinoids are also associated with the activation of CB1R. The recent discovery of inhibitory CB2 receptors in the ventral tegmental area (VTA) DA neurons and their inhibitory role in the dopaminergic circuit, leading to reduced DA release in nucleus accumbens (NAc), as well as a receptor modulating glial and microglia function in the CNS, has created a new opportunity for targeting this pathway for therapeutic development. With support from a U18 NIDA pilot grant for the past year, we have successfully identified a lead series of novel chemical entities (NCEs) that display functional selectivity for cyclase over arrestin (i.e., biased) and are also very selective for CB2R with minimal activity for CB1R. Our lead candidate has good oral absorption, brain penetration and, in animal models, reverses the addictive behavior of mice. This proposal aims to further optimize our lead compound as a preclinical/clinical candidate for the treatment of MUD. While displaying excellent selectivity for CB2R over CB1R, our lead compound has residual arrestin activity and needs further PK optimization. We have put together a panel of multidisciplinary experts covering CNS pharmacology, medicinal chemistry, biology, and preclinical and clinical addiction medicine and psychiatry to further support the development of this class of compounds with the help of the Blueprint Neurotherapeutics Network (BPN) before testing in humans.