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。2019年，2040万美国老年人 12岁或12岁以上的人有药物使用障碍。大约160万人患有阿片类药物使用障碍， 平均每天导致超过136人服药过量死亡。兴奋剂滥用也是一个重要因素。 这场社会危机的广度和严重性，100万人患有甲基苯丙胺使用障碍(MUD) 另有100万人死于可卡因使用障碍。甲基苯丙胺和可卡因是目前的主要原因 非法药物阿片类药物背后的过量死亡。美沙酮和丁丙诺啡是广泛使用的治疗方法 用于阿片成瘾，但目前还没有被批准的药物使用障碍的药物治疗 (南加州)。因此，迫切需要开发针对SUD的药理干预措施。医用大麻 与阿片类药物处方率和死亡率的降低有关，临床前研究表明 大麻类物质会影响类似上瘾的行为。这些作用被认为是由大麻素介导的。 大脑中的感受器。大麻素受体1和2(分别为CB1R和CB2R)是 内源性大麻素系统在调节中枢多巴胺(DA)水平中起关键作用 系统(CNS)。大麻和非选择性大麻素如THC可以激活CB1R和CB2R。 虽然已经投入了大量的努力来了解CB1R在这个DA系统中的作用，但上瘾的 而大麻素的精神活性也与CB1R的激活有关。最近的 腹侧被盖区DA神经元中抑制性CB2受体的发现及其抑制作用 在多巴胺能回路中，导致伏核(NAC)中DA释放减少，以及一种受体 调节中枢神经系统中的神经胶质细胞和小胶质细胞的功能，为靶向这一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 鉴定了一系列新的化学实体(NCEs)，它们对环化酶具有功能选择性 Arrestin(即偏向的)，对CB2R也非常有选择性，对CB1R的活性最低。我们的主要候选人 具有良好的口服吸收和脑渗透，并在动物模型中，逆转小鼠的成瘾行为。 这项建议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。 一堆泥巴。虽然我们的先导化合物对CB2R表现出比CB1R更好的选择性，但仍有残留芳烃 活跃度，需要进一步的PK优化。我们已经组建了一个由多学科专家组成的小组， 中枢神经系统药理学、药物化学、生物学以及基础和临床成瘾医学和 精神病学在蓝图的帮助下进一步支持这类化合物的开发 神经治疗网络(BPN)在人体试验之前。

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.