Treatment for cannabis use disorder

大麻使用障碍的治疗

• 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
• 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

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.

摘要 我们的目标是为影响超过400万人的大麻使用障碍（CUD）开发一种创新的药物疗法 美国人我们建议开发一种新的第二代大麻素1的PARTIAL反向激动剂 受体（CB 1），具有良好的行为特征的CUD。大麻素是第二大滥用类别， 目前世界上还没有FDA批准的用于CUD的药物，这使得这一领域的需求迫切。的 大麻和合成大麻素的精神活性作用由中枢CB 1受体的激活引起。 阻断滥用药物的奖励和渴望特性是一种得到充分验证和接受的策略， 物质使用障碍（SUD），没有强烈的不良身体戒断成分。利莫那班是一种强效的 CB 1受体的完全反向激动剂，在欧洲被批准作为抗肥胖剂。不幸的是， 利莫那班在约6%的使用者中产生了不良的烦躁反应--这种反应可能是由于持续的高脑 暴露和有效的反向激动，这导致其最终停止。在人类研究中，利莫那班 在治疗慢性溃疡性结肠炎的许多方面都有效。Artiam Bio正在开发下一代CB 1拮抗剂 与利莫那班和先前的临床试验相比， 候选人Artiam Bio的先导化合物是一种口服活性，强效和选择性的CB 1部分反向激动剂， 有限的大脑渗透。该化合物在功能上与利莫那班一样有效，但不产生 啮齿动物研究中的烦躁/快感缺乏。通过三个目标提出了该化合物的进一步发展。 通过目标1，将使用建立的化学路线利用以下合成约500 g化合物： 阿蒂亚姆的经验与同类。通过目标2和3，将开展剂量范围确定毒理学研究。 在两个种属中进行，并将确定毒代动力学参数。成功完成第一阶段 SBIR申请将为GLP监管研究和Artiam领导的其他IND使能活动铺平道路 候选人CUD