Target Specificity of Tabernanthalog Treatment in Opioid Use Disorder

Tabernantalog 治疗阿片类药物使用障碍的目标特异性

• 批准号: 10512599
• 负责人: Jasper Heinsbroek
• 金额: $ 10.34万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2023-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10512599
• 关键词: Acute; Agonist; Alcohol abuse; Alcohol consumption; Alcohols; Attention; Behavioral; Binding; Brain; Buprenorphine; Cardiac; Cardiotoxicity; Chemicals; Chronic; Clinic; Cognitive; Consumption; Cues; Decision Making; Development; Drug usage; Engineering; FDA approved; Food; Goals; Growth; HTR2A gene; Hallucinations; Hallucinogens; Heroin; Home; Ibogaine; Incidence; Ligands; Mediating; Mental disorders; Methadone; Modeling; Motivation; N,N-Dimethyltryptamine; Naloxone; Naltrexone; Neuronal Plasticity; Neurotrophic Tyrosine Kinase Receptor Type 2; Opioid; Opioid Receptor; Outcome; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Play; Pre-Clinical Model; Prefrontal Cortex; Property; Relapse; Rewards; Rodent Model; Role; Safety; Self Administration; Serotonin; Serotonin Agents; Serotonin Receptor 5-HT2A; Serotonin Receptor 5-HT2B; Site; Specificity; Substance Use Disorder; System; Testing; Therapeutic; Therapeutic Effect; Translations; Treatment Efficacy; Vertebral column; addiction; alcohol seeking behavior; alcohol use disorder; analog; antagonist; base; cognitive reappraisal; comorbidity; density; drug craving; drug discovery; drug relapse; endogenous opioids; executive function; functional restoration; genetic approach; gray matter; in vivo; insight; interest; multiple drug use; neural circuit; neuroadaptation; novel; opioid therapy; opioid use; opioid use disorder; opioid withdrawal; patient population; pre-clinical; protective effect; receptor; receptor binding; relating to nervous system; screening; serotonin 5 receptor; serotonin receptor; side effect; substance use treatment

PROJECT SUMMARY Opioid use disorder (OUD) is characterized by persistent drug seeking often accompanied by a loss of interest in natural rewards. Current FDA-approved treatments for OUD target the endogenous opioid system directly, either as substitution therapies (e.g. buprenorphine, methadone) or antagonists that oppose opioid effects (e.g. naltrexone, naloxone). Although these therapies have helped reduce overall harm, they are rarely a cure for OUD. As the seat of executive function, the PFC plays an integral role in decision-making, impulse control, and the cognitive regulation of drug craving and relapse. Thus, novel compounds capable of promoting neural plasticity to augment or restore PFC function possess enormous therapeutic potential for treating substance use disorders (SUDs). Structural plasticity in the PFC could produce long-lasting protective effects against relapse, and would reduce the need for chronic medication. Plasticity-promoting, psychoplastogenic compounds may also have broad-spread restorative effects on downstream neural circuits, and may normalize aberrant plasticity and neural activity across addiction networks. Psychedelic compounds including 5-methoxy-N,N- dimethyltryptamine (5-MeO-DMT) and ibogaine potently induce spine growth in the PFC in a serotonin 5-HT2A receptor-dependent manner. This class of drugs also elicits long-lasting anti-addictive properties across a wide variety of SUDs, but their side effects including hallucinations and cardiotoxicity limit their therapeutic potential. To overcome these barriers to therapeutic application, we engineered a safer psychoplastogenic 5-HT2A receptor ligand called tabernanthalog (TBG), which chemically resembles ibogaine and 5-MeO-DMT, yet lacks hallucinogenic effects and cardiotoxicity and does not bind to opioid receptors. We demonstrated that TBG decreases both alcohol and heroin consumption and reduces relapse rates long-term in a heroin self- administration model after a single treatment. However, the pharmacological and brain-specific mechanisms that mediate these anti-addictive effects are currently unknown. The overarching objectives of this project are to determine the in vivo receptor targets mediating the anti-addictive effects of TBG, and whether TBG’s psychoplastogenic effects within addiction neural circuitry is a mechanism of action for TBG therapy. Establishing the anti-addictive mechanism of TBG will aid continued drug discovery of more potent and selective compounds for treating addiction and may help identify patient populations that are likely to respond to treatment. In addition to identifying the role of serotonin receptors and structural plasticity in the effect of TBG, this proposal will also screen the therapeutic potential of TBG in a polydrug (opioid and alcohol) use model and determine the specificity of TBG therapy for opioids versus natural rewards. Information gained from this project will provide insight into TBG’s potential as an anti-OUD therapeutic and its mechanism of action, thus allowing us to further optimize TBG and related compounds for translation to the clinic.

项目摘要 阿片类药物使用障碍（OUD）的特征是持续的药物寻求，通常伴有兴趣丧失 自然的回报。目前FDA批准的OUD治疗直接靶向内源性阿片系统， 作为替代疗法（例如丁丙诺啡、美沙酮）或对抗阿片样物质作用的拮抗剂（例如， 纳洛酮、纳洛酮）。虽然这些疗法有助于减少整体伤害，但它们很少能治愈 OUD。作为执行功能的所在地，前额叶皮层在决策、冲动控制和 对药物渴求和复吸的认知调节。因此，能够促进神经细胞增殖的新化合物， 增强或恢复PFC功能的可塑性在治疗物质使用方面具有巨大的治疗潜力 疾病（SUD）。前额叶皮层的结构可塑性可以产生长期的保护作用，防止复发， 并将减少对慢性药物的需求。促进可塑性的精神可塑性化合物可 对下游神经回路也有广泛的恢复作用，并可能使异常的可塑性正常化。 和神经活动之间的联系。迷幻剂化合物，包括5-甲氧基-N，N- 二甲基色胺（5-MeO-DMT）和伊波替尼在5-羟色胺5-HT 2A中有效诱导PFC中的棘生长。 受体依赖的方式。这类药物还在广泛的领域具有持久的抗成瘾特性。 SUD的种类很多，但它们的副作用，包括幻觉和心脏毒性，限制了它们的治疗潜力。 为了克服这些治疗应用的障碍，我们设计了一种更安全的精神致塑性5-HT 2A， 受体配体称为tabernanthropy（TBG），其化学上类似于iboclavin和5-MeO-DMT，但缺乏 致幻作用和心脏毒性，并且不与阿片受体结合。我们证明了TBG 减少酒精和海洛因的消耗，并降低海洛因自我长期复发率， 单次治疗后的给药模型。然而，药理学和大脑特异性机制， 介导这些抗成瘾作用目前尚不清楚。该项目的总体目标是 确定介导TBG抗成瘾作用的体内受体靶点，以及TBG是否 成瘾神经回路内的精神可塑性效应是TBG治疗的作用机制。建立 TBG的抗成瘾机制将有助于继续发现更有效和更有选择性的化合物 用于治疗成瘾，并可能有助于识别可能对治疗有反应的患者群体。此外 为了确定5-羟色胺受体和结构可塑性在TBG效应中的作用，该建议还将 在多药（阿片类药物和酒精）使用模型中筛选TBG的治疗潜力，并确定特异性 TBG治疗阿片类药物与自然奖励的对比。从该项目中获得的信息将提供以下见解 TBG作为抗OUD治疗剂的潜力及其作用机制，从而使我们能够进一步优化 TBG和相关化合物用于临床。