Target Specificity of Tabernanthalog Treatment in Opioid Use Disorder

项目总结 阿片类药物使用障碍(OUD)的特征是持续寻求药物，常常伴随着兴趣的丧失。 在自然的奖励中。目前FDA批准的治疗OUD的药物直接针对内源性阿片系统， 作为替代疗法(如丁丙诺啡、美沙酮)或对抗阿片类药物效应的拮抗剂(如 纳曲酮、纳洛酮)。尽管这些疗法有助于减少总体伤害，但它们很少能治愈 奥德。作为执行职能的所在地，PFC在决策、冲动控制和 药物渴求和复吸的认知调节。因此，能够促进神经功能的新型化合物 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 精神障碍(肥皂泡)。PFC的结构可塑性可以产生长期的预防复发的效果， 并将减少对慢性药物的需求。促进可塑性、精神塑形的化合物可能 对下游神经回路也有广泛的恢复作用，并可能使异常可塑性正常化 以及成瘾网络中的神经活动。迷幻化合物包括5-甲氧基-N，N- 二甲基色胺(5-MeO-DMT)和伊波甘有效地诱导5-HT2A型5-羟色胺在PFC内的脊椎生长 受体依赖方式。这类药物还在广泛的范围内产生持久的抗成瘾特性 肥皂水种类繁多，但其副作用，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致精神病5-HT2a 受体配体tBG，化学上类似于伊波甘氨酸和5-MeO-DMT，但缺乏 致幻作用和心脏毒性，不与阿片受体结合。我们演示了TBG 减少酒精和海洛因的消费，并降低海洛因本身的长期复发率 单次给药后给药模式。然而，药物和大脑特有的机制 调解这些抗成瘾作用目前尚不清楚。该项目的总体目标是 确定通络颗粒抗成瘾作用的体内受体靶点，以及通络颗粒是否具有抗成瘾作用 成瘾神经回路中的精神再生效应是TBG治疗的一种作用机制。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，这一建议还将 在多药(阿片类药物和酒精)使用模型中筛选TBG的治疗潜力并确定其特异性 阿片类药物的TBG疗法与自然奖励的对比。从这个项目中获得的信息将提供对 TBG作为一种抗OUD药物的潜力及其作用机制，从而使我们能够进一步优化 TBG和相关化合物用于翻译到临床。

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.