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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要阿片类药物使用障碍 (OUD) 的特点是持续寻求药物，通常伴有兴趣丧失目前 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、美沙酮）或对抗阿片类药物作用的拮抗剂（例如阿片类药物）尽管这些疗法有助于减少总体伤害，但它们很少能治愈疾病。 OUD 作为执行功能的所在地，在决策、冲动控制和决策中发挥着不可或缺的作用。因此，新的化合物能够促进神经系统的发展。增强或恢复 PFC 功能的可塑性对于治疗药物滥用具有巨大的治疗潜力 PFC 的结构可塑性可以产生持久的预防复发的保护作用，并可能减少对促进可塑性、精神塑性化合物的长期药物的需求。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以及成瘾网络中的神经活动，包括 5-甲氧基-N,N-。二甲基色胺 (5-MeO-DMT) 和伊博加因在血清素 5-HT2A 中有效诱导 PFC 中的棘生长此类药物还具有多种受体依赖性的持久抗成瘾特性。 SUD 种类繁多，但其副作用（包括幻觉和心脏毒性）限制了其治疗潜力。为了克服这些治疗应用的障碍，我们设计了一种更安全的心塑性 5-HT2A 称为 tabernanthalog (TBG) 的受体配体，其化学性质类似于伊博加因和 5-MeO-DMT，但缺乏我们证明了 TBG 具有致幻作用和心脏毒性，并且不与阿片受体结合。减少酒精和海洛因的消耗，并降低海洛因自我戒毒的长期复吸率然而，单次治疗后的药理学和大脑特异性机制。目前尚不清楚如何调节这些抗成瘾作用。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标，以及 TBG 是否成瘾神经回路中的心理塑性效应是 TBG 治疗的一种作用机制。 TBG 的抗成瘾机制将有助于继续发现更有效和更具选择性的化合物用于治疗成瘾，并可能有助于确定可能对治疗有反应的患者群体。为了确定 5-羟色胺受体和结构可塑性在 TBG 效果中的作用，该提案还将在多种药物（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从该项目中获得的信息将有助于深入了解阿片类药物的 TBG 疗法与自然奖励的比较。 TBG 作为抗 OUD 疗法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转化。