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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要美国目前面临严重的药物滥用问题。 2019 年，2040 万美国人老龄化 12 岁或以上患有药物滥用障碍。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。滥用兴奋剂也是一个重要因素这场社会危机的蔓延和严重性，100万人患有甲基苯丙胺使用障碍（MUD）另有 100 万人因可卡因使用障碍而死亡。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用于治疗阿片类药物成瘾，但目前尚无批准的药物治疗兴奋剂使用障碍（南苏丹）。因此，迫切需要开发针对 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的降低有关，临床前研究表明大麻素会影响成瘾行为。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 CB1R 和 CB2R）是内源性大麻素系统在调节中枢神经多巴胺 (DA) 水平方面发挥着至关重要的作用系统（中枢神经系统）。大麻和非选择性大麻素（例如 THC）可以激活 CB1R 和 CB2R。虽然人们投入了大量精力来理解 CB1R 在这个 DA 系统中的作用，但成瘾性大麻素的精神活性也与 CB1R 的激活有关。最近的腹侧被盖区 (VTA) 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，导致伏隔核 (NAc) 以及受体中的 DA 释放减少调节中枢神经系统中的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开发。在去年 U18 NIDA 试点拨款的支持下，我们成功地确定了一系列先导的新型化学实体（NCE），它们对环化酶表现出功能选择性视紫红质抑制蛋白（即有偏差），对 CB2R 也具有很强的选择性，而对 CB1R 的活性极小。我们的主要候选人具有良好的口服吸收性、脑渗透性，在动物模型中可以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治疗的临床前/临床候选药物泥浆。虽然我们对 CB2R 的选择性优于 CB1R，但我们的先导化合物具有残留的抑制蛋白活动，需要进一步PK优化。我们组建了一个由多学科专家组成的小组，涵盖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和精神病学在蓝图的帮助下进一步支持此类化合物的开发神经治疗网络（BPN）在人体测试之前。