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Exploiting Biased Agonism at the Ghrelin Receptor (GHSR1a) for Opioid Addiction

利用 Ghrelin 受体 (GHSR1a) 的偏向激动来治疗阿片类药物成瘾

基本信息

批准号：
10404081
负责人：
Joshua D Gross
金额：
$ 6.98万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10404081
关键词：
Actins Agonist Animal Model Attenuated Automobile Driving Behavior Biochemical Biological Assay Buprenorphine Cell model Clinical Cocaine Collaborations Confocal Microscopy Coupled Data Dendritic Spines Desire for food Development Diagnosis Disease Dopamine Dopaminergic Agents Drug Screening Drug Targeting Eating Exhibits Extinction (Psychology)F-Actin Food Future G-Protein-Coupled Receptors GHS-R1a GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Goals Injections Investigation Knockout Mice Lead Ligands Maintenance Measures Mediating Methadone Microscopy Modeling Molecular Motivation Mus Naloxone Naltrexone National Center for Advancing Translational Sciences National Institute of Drug Abuse Neuronal Plasticity Neurons Nucleus Accumbens Opiate Addiction Opioid Outcome Palate Pathway interactions Patients Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Physiological Procedures Process Public Health Relapse Research Rewards Role Self Administration Signal Pathway Signal Transduction Statistical Data Interpretation Stimulus Stress Fibers Symptoms System Techniques Testing Therapeutic Training Ventral Tegmental Area Viral Vector Visualization addiction analog antagonist base beta-arrestin brain tissue combat cost density dopamine transporter dopaminergic neuron drug of abuse experience feeding ghrelin ghrelin receptor growth hormone secretagogue receptor hedonic improved large datasets mesolimbic system motivated behavior mouse model nanobodies novel novel therapeutic intervention novel therapeutics opioid abuse opioid epidemic opioid use disorder peptide hormone pre-clinical prevent protein protein interaction recruit selective prevention side effect socioeconomics tool trafficking

项目摘要

Abstract In the U.S., the number of Opioid Use Disorder (OUD) diagnoses has exceeded 2 million. Although existing OUD medications (e.g., methadone, buprenorphine, naltrexone) ameliorate OUD symptoms and relapse rates, they are not without problematic side-effects and medication discontinuation remains an issue. Consequently, NIDA has prioritized the development of novel medications to prevent and/or treat OUD. Among NIDA's "10 most wanted" pharmacologic targets for OUD is the ghrelin receptor, growth hormone secretagogue receptor 1a (GHSR1a). GHSR1a is densely expressed within dopamine (DA) neurons of mesolimbic ("reward") system and its activation leads to increased DA release and enhanced motivation to acquire rewarding/reinforcing stimuli (e.g., food, drugs of abuse). Like other GPCRs, the physiological effects of GHSR1a depend whether G protein- or b-arrestin (barr)-dependent signaling pathways are preferentially engaged, a process known as functional selectivity (or biased agonism). Considerable prior evidence supports that leveraging GPCR functional selectivity may provide a means by which to enhance pharmacotherapeutic efficacy and/or diminish deleterious side- effects. The Caron group has previously shown that GHSR1a antagonism blocks hyperlocomotion in cocaine- sensitized mice via a barr-dependent mechanism in DA neurons. Additionally, the Caron group has also demonstrated that GHSR1a-induced actin stress fiber formation -- a molecular process integral to the neuroadaptive changes produced by reinforcing substances -- is barr-mediated. In a large-scale drug screen for novel GHSR1a ligands coupled with medicinal chemistry, the Caron group in collaboration with NCATS, has identified a lead compound, 8279, which acts as a GHSR1a-selective G protein-biased agonist and thus, attenuates GHSR1a-mediated barr signaling. Initial data shows that 8279 reduces basal hyperlocomotion in dopamine transporter knockout (DAT KO) mice (an animal model of hyperDAergia), but does not affect hedonic feeding. The objectives of this application are to delineate the mechanisms of G protein-biased ligands at GHSR1a and interrogate their therapeutic potential in mouse models of opioid abuse. The central hypothesis is that G protein-biased GHSR1a agonism attenuates opioid-induced neuroplasticity and self-administration via reduced barr recruitment and/or signaling following GHSR1a activation. This hypothesis will be tested by pursuing three specific aims using 8279, or its derivatives, as our primary tool compound: 1) Elucidate the biochemical mechanisms underlying GHSR1a biased signaling, 2) Identify the effects of GHSR1a biased signaling on neuroplasticity, and 3) Evaluate the effects of GHSR1a biased signaling on opioid-induced behavior. These three aims will be tested using established GPCR trafficking, protein-protein interaction, and signaling assays, viral vector-based measures of neuroplasticity in brain tissue, and mouse self-administration. These studies are significant and novel in that they will provide a thorough preclinical investigation into the potential therapeutic utility of exploiting GHSR1a functional selectivity for the prevention and/or treatment of OUD.

摘要在美国，阿片类药物使用障碍（OUD）的诊断数量已超过200万。虽然现有的药物（例如，美沙酮、丁丙诺啡、纳洛酮）改善OUD症状和复发率，并不是没有问题的副作用，停药仍然是一个问题。因此，NIDA 已经优先开发预防和/或治疗OUD的新药。在NIDA的“10个最 OUD的“需要的”药理学靶点是生长激素释放肽受体，生长激素促分泌素受体1a （GHSR 1a）。GHSR 1a在中脑边缘（“奖赏”）系统的多巴胺（DA）神经元内密集表达，它的激活导致DA释放增加，并增强获得奖励/强化刺激的动力 (e.g.,食物、药物滥用）。与其他GPCR一样，GHSR 1a的生理效应取决于G蛋白- 或b-抑制蛋白（巴尔）依赖性信号通路优先参与，这一过程被称为功能性选择性（或偏向激动作用）。大量先前证据支持利用GPCR功能选择性可以提供一种增强药效和/或减少有害副作用的方法，方面的影响. Caron小组先前已经表明，GHSR 1a拮抗作用阻断了可卡因中的过度运动- 致敏小鼠通过barr依赖机制在DA神经元。此外，Caron集团还证明GHSR 1a诱导的肌动蛋白应力纤维形成--一个与细胞增殖相关的分子过程，由强化物质产生的神经适应性变化--是barr介导的。在大规模的药物筛选中，新型GHSR 1a配体与药物化学结合，Caron小组与NCATS合作，确定了一种先导化合物8279，它作为GHSR 1a选择性G蛋白偏向激动剂，因此，减弱GHSR 1 α介导的巴尔信号传导。初步数据显示，8279减少了基础过度运动，多巴胺转运蛋白敲除（DAT KO）小鼠（一种高DAergia的动物模型），但不影响快感喂食本申请的目的是描述G蛋白偏向配体在 GHSR 1a，并询问其在阿片类药物滥用小鼠模型中的治疗潜力。核心假设 G蛋白偏向的GHSR 1a激动作用减弱阿片类药物诱导的神经可塑性和自我给药， GHSR 1 a活化后减少的巴尔募集和/或信号传导。这一假设将由以下人员进行检验：使用8279或其衍生物作为我们的主要工具化合物，追求三个具体目标：1）阐明 GHSR 1a偏置信号的生化机制，2）确定GHSR 1a偏置信号的作用信号传导对神经可塑性的影响，以及3）评估GHSR 1a偏向信号传导对阿片样物质诱导的行为的影响。这三个目标将使用已建立的GPCR运输，蛋白质-蛋白质相互作用和信号转导进行测试测定、基于病毒载体的脑组织神经可塑性测量和小鼠自身给药。这些研究是重要的和新颖的，因为它们将提供对潜在的利用GHSR 1a功能选择性预防和/或治疗OUD的治疗用途。