Treatment for cannabis use disorder

大麻使用障碍的治疗

基本信息

批准号：
10546566
负责人：
HERBERT H SELTZMAN
金额：
$ 31.99万
依托单位：
ARTIAM BIO INC.
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：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10546566
关键词：
Adverse effects Affect Agonist American Anhedonia Animals Anti-Obesity Agents Area Award Behavioral Benign Brain CNR1 gene CNR2 gene Canis familiaris Cannabinoids Cannabis Cells Chemicals Clinical Data Cognitive Therapy Development Dose Emergency department visit Emotional Europe FDA approved Failure G-Protein-Coupled Receptors Generations Goals Human Immune Lead Legal patent Marijuana Maximum Tolerated Dose Oral Organ Outcome Penetration Peripheral Pharmaceutical Preparations Pharmacotherapy Phase Physiological Plasma Production Property Rattus Receptor Signaling Research Design Rewards Rodent Route Self Stimulation Signal Transduction Small Business Innovation Research Grant Substance Use Disorder Tetrahydrocannabinol Therapeutic Toxic effect Toxicokinetics Toxicology Withdrawal addiction antagonist base behavioral study chemical synthesis clinical candidate cohort craving design drug discrimination drug of abuse dysphoria experience imaging study innovation interest lead candidate marijuana legalization marijuana use marijuana use disorder next generation novel novel therapeutics preclinical study psychologic receptor rimonabant scale up small molecule social synthetic cannabinoid welfare

项目摘要

Abstract Our goal is to develop an innovative pharmacotherapy for cannabis use disorder (CUD) that affects over 4 million Americans. We propose to develop a novel second generation PARTIAL inverse agonist of the cannabinoid 1 receptor (CB1) that has a benign behavioral profile for CUD. Cannabinoids are the second most abused class of drug in the world and there is no FDA approved medication for CUD -- making this an area of urgent need. The psychoactive effects of cannabis and synthetic cannabinoids result from activation of central CB1 receptors. Blocking the rewarding and craving properties of drugs of abuse is a well-validated and accepted strategy for substance use disorders (SUD) without a strong adverse physical withdrawal component. Rimonabant is a potent FULL inverse agonist of the CB1 receptor that was approved in Europe as an anti-obesity agent. Unfortunately, rimonabant produced adverse dysphoric effects in ~6% of users -- effects likely due to sustained high brain exposure and potent inverse agonism, which led to its eventual discontinuation. In human studies, rimonabant was efficacious in treating many aspects of CUD. Artiam Bio is developing the next generation of CB1 antagonists that are expected to have a superior adverse effect profile compared to rimonabant and previous clinical candidates. Artiam Bio’s lead compound is an orally active, potent, and selective CB1 partial inverse agonist with limited brain penetration. This compound is functionally as efficacious as rimonabant but produces no dysphoria/anhedonia in rodent studies. Further development of this compound is proposed through three aims. Through aim 1, ~500 g of the compound will be synthesized using an established chemical route leveraging upon Artiam’s experience with a congener. Through aims 2 and 3, dose range finding toxicological studies will be performed in two species and toxicokinetic parameters will be established. Successful completion of this phase 1 SBIR application will pave the way for GLP regulatory studies and other IND-enabling activities of Artiam’s lead candidate for CUD.

抽象的我们的目标是开发用于大麻使用障碍（CUD）的创新药物治疗，该疗法影响超过400万美国人。我们建议开发大麻素1的新型第二代部分反激动剂受体（CB1）具有用于CUD的良性行为特征。大麻素是第二大虐待类世界上的药物，没有FDA批准的CUD药物 - 使这一领域迫切需要。这大麻和合成大麻素的精神活性作用是由中央CB1受体的激活引起的。阻止滥用药物的奖励和渴望的特性是一项经过验证的公认策略物质使用障碍（SUD）没有强大的不良物理戒断成分。里蒙纳巴特是一个有力的 CB1受体的完全反向激动剂在欧洲被批准为抗肥胖剂。很遗憾，利莫班班人在约6％的用户中产生了不良烦躁不安的影响 - 可能是由于持续的高脑而引起的。暴露和潜在的反向激动剂，导致其最终中断。在人类研究中有效地治疗CUD的许多方面。 Artiam Bio正在发展下一代CB1拮抗剂与Rimonabant和先前的临床相比候选人。 Artiam Bio的铅大院是一种口服，潜力和选择性的CB1部分反向激动剂，有限的大脑穿透。该化合物在功能上与Rimonabant一样有效，但会产生NO 啮齿动物研究中的吞咽困难/anhedonia。该化合物的进一步开发是通过三个目标提出的。通过AIM 1，将使用确定的化学路线合成约500 g的化合物 Artiam与同类物的经历。通过目标2和3，剂量范围发现毒理学研究将是将建立在两个物种中进行的，并建立有毒动力学参数。成功完成此阶段1 SBIR的应用将为GLP监管研究和Artiam的其他指定活动铺平道路 CUD的候选人。