Development of selective cannabinoid receptor 2 agonists for treatment of addiction

开发用于治疗成瘾的选择性大麻素受体 2 激动剂

• 批准号: 10467887
• 负责人: Mehrdad Shamloo
• 金额: $ 66.2万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-19 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10467887
• 关键词: Addictive Behavior; Affect; Agonist; American; Americas; Amphetamine Addiction; Animal Model; Animals; Arrestins; Behavior; Biological Assay; Biology; Brain; Buprenorphine; CNR1 gene; CNR2 gene; Cannabinoids; Cells; Cessation of life; Chemicals; Clinical; Clinical Trials; Cocaine; Cocaine use disorder; Cyclic AMP; Data; Development; Dopamine; Dose; Engineering; Epidemic; FDA approved; Face; Failure; Feasibility Studies; Formulation; Funding; Goals; Grant; Heroin; Heroin Dependence; Human; Hyperactivity; Illicit Drugs; In Vitro; Intervention; Lead; MAPK3 gene; Manufactured Materials; Marijuana; Maximum Tolerated Dose; Mediating; Medical Marijuana; Medicine; Methadone; Methamphetamine; Methamphetamine use disorder; Microglia; Modeling; Mus; National Institute of Drug Abuse; Neuraxis; Neurons; Nucleus Accumbens; Opiate Addiction; Opioid; Oral; Outcome; Pain; Pathway interactions; Penetration; Phagocytosis; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phase; Phase I Clinical Trials; Play; Polymorph; Preparation; Property; Psychiatry; Rattus; Residual state; Rodent; Role; Safety; Seeds; Self Administration; Severities; Signal Transduction; Sodium Chloride; Specificity; Stimulant; Substance Use Disorder; Testing; Toxicogenetics; Toxicology; Validation; Ventral Tegmental Area; absorption; addiction; aged; analog; animal efficacy; base; beta-arrestin; cannabinoid receptor; chemical synthesis; clinical candidate; clinical development; conditioned place preference; course development; desensitization; design; dopamine system; dopaminergic neuron; drug discovery; efficacy study; endogenous cannabinoid system; illicit opioid; in vivo; lead candidate; lead optimization; lead series; multidisciplinary; novel; opioid epidemic; opioid use disorder; overdose death; phase 1 designs; pre-clinical; preclinical development; preclinical study; prescription opioid; programs; receptor; research clinical testing; safety and feasibility; safety study; scale up; screening; social; socioeconomics; species difference; stimulant abuse; stimulant dependence; stimulant use disorder; therapeutic development; therapy development

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.

项目摘要 美国目前面临着毒品使用障碍的严重流行。 2019年，有2040万美国人年龄 12岁或以上患有药物使用障碍。大约有160万人患有阿片类药物使用障碍，这 平均每天导致超过136例过量死亡。刺激性滥用也是重要的贡献者 这场社会危机的扩展和严重程度，有100万甲基苯丙胺使用障碍（MUD） 还有100万可卡因使用障碍。甲基苯丙胺和可卡因目前是主要原因 阿片类药物的过量死亡因非法药物而死亡。美沙酮和丁丙诺啡是广泛使用的治疗方法 对于阿片类药物成瘾，但目前尚无批准的药理学治疗方法 （SUD）。因此，迫切需要开发SUD的药理干预措施。医用大麻 与阿片类药物处方率和死亡的降低有关，临床前研究表明 大麻素会影响上瘾的行为。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CB1R和CB2R）是 内源性大麻素系统，并在中枢神经中调节多巴胺（DA）水平中起着至关重要的作用 系统（CNS）。大麻和非选择性大麻素（例如THC）可以激活CB1R和CB2R。 尽管已经投入了广泛的努力来了解CB1R在此DA系统中的作用，但令人上瘾 大麻素的精神活性特性也与CB1R的激活有关。最近 发现腹侧盖区域（VTA）DA神经元及其抑制作用的抑制性CB2受体及其抑制作用 在多巴胺能回路中，导致伏隔核（NAC）的DA释放降低，并且受体 调节中枢神经系统中的神经胶质和小胶质细胞功能，为针对此途径创造了一个新的机会 用于治疗发展。在过去一年的U18 NIDA飞行员赠款的支持下，我们已经成功 鉴定了一系列新型化学实体（NCE），该实体（NCES）显示了环化酶的功能选择性 逮捕蛋白（即有偏见），对于CB2R而言，CB1R活性最低的CB2R也非常有选择性。我们的主要候选人 具有良好的口服吸收，脑渗透，并且在动物模型中，可以逆转小鼠的成瘾行为。 该建议旨在进一步优化我们的铅化合物作为治疗的临床前/临床候选者 泥。在对CB1R上的CB2R表现出极好的选择性时，我们的铅化合物具有残留逮捕 活动和需要进一步的PK优化。我们整理了一个跨学科专家的小组 CNS药理学，药物化学，生物学以及临床前和临床成瘾医学以及 精神病学以进一步支持此类化合物的开发 在人类测试之前，神经疗法网络（BPN）。