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）的特征是寻求持续的药物通常伴随着失去利益 自然奖励。当前的FDA批准的OUD治疗直接针对内源性阿片类药物系统， 作为替代疗法（例如，丁丙诺啡，方法加多酮）或反对阿片类药物作用的拮抗剂（例如 尽管这些疗法有助于减少整体伤害，但它们很少可以治愈 Oud。作为行政职能的所在地，PFC在决策，冲动控制和 毒品渴望和救济的认知调节。那是能够促进神经元的新颖化合物 可塑性以增强或恢复PFC功能潜在的治疗药物的巨大治疗潜力 疾病（SUDS）。 PFC中的结构可塑性可能会产生持久的保护作用，以防止缓解， 并减少对慢性药物的需求。促进性，精神构成化合物可能 还对下游神经元电路具有广泛的恢复作用，并且可能使异常可塑性正常化 和跨成瘾网络的神经活动。迷幻化合物，包括5-甲氧基-N，N- 二甲基苯丙胺（5-meo-DMT）和ibogaine可能诱导5-羟色胺5-HT2A的PFC脊柱生长 接收器依赖性方式。这类药物还引起了宽阔的抗鬼特性 多种泡沫，但它们的副作用包括幻觉和心脏毒性限制了其治疗潜力。 为了克服这些热应用的障碍，我们设计了一种更安全的精神碎裂性5-HT2A 受体配体称为tabernthalog（TBG），化学上类似于ibogaine和5-meo-dmt，但缺乏 致幻作用和心脏毒性，不与阿片受体结合。我们证明了TBG 降低酒精和海洛因消耗，并长期降低海洛因自我的接力率 一次治疗后的管理模型。但是，药物和大脑特异性机制 目前介导这些反添加作用的效果尚不清楚。该项目的总体目标是 确定体内受体的靶标介导TBG的抗可怕作用，以及TBG是否 成瘾神经回路中的精神构成作用是TBG治疗的一种作用机理。建立 TBG的抗添加机制将有助于持续的药物发现更多的潜力和选择性化合物 用于治疗成瘾，并可能有助于确定可能对治疗反应的患者人群。此外 为了确定5-羟色胺受体和结构可塑性在TBG效果中的作用，该建议还将 筛选TBG在多药（阿片类药物和酒精）中使用模型的治疗潜力并确定特异性 阿片类药物与自然奖励的TBG治疗。从这个项目中获得的信息将提供有关 TBG作为一种反淘汰疗法及其作用机理的潜力，从而使我们能够进一步优化 TBG和相关化合物，用于转化为诊所。