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.

抽象的在美国，阿片类药物使用障碍（OUD）的诊断数量已超过200万。虽然存在药物（例如美沙酮，丁丙诺啡，纳曲酮）改善了OUD症状和复发率，它们并非没有问题的副作用和停用药物仍然是一个问题。因此，尼达优先考虑开发新的药物来预防和/或治疗OUD。在NIDA的“最多10个想要的“ OUD的药理学靶标是生长素受体，生长激素秘密受体1a （GHSR1A）。 GHSR1A在中唇（“奖励”）系统的多巴胺（DA）神经元中密集表达它的激活导致DA的释放增加并增强了获得奖励/增强刺激的动机（例如，食物，滥用药物）。像其他GPCR一样，GHSR1A的生理效应取决于G蛋白 - 或B-arrestin（Barr）依赖性信号通路优先参与，这一过程称为功能选择性（或偏见激动剂）。大量的先前证据支持利用GPCR功能选择性可以提供一种增强药物治疗功效和/或降低有害侧面的手段效果。 Caron组先前已经表明，GHSR1A拮抗作用阻碍了可卡因的超替代。通过DA神经元中的BARR依赖机制敏化小鼠。此外，卡伦集团也有证明GHSR1A诱导的肌动蛋白应激纤维形成 - 一种与通过增强物质产生的神经适应性变化 - 是巴尔介导的。在大规模的药物屏幕中新颖的GHSR1A配体加上与NCATS合作的Caron Group的药物化学的配体鉴定出铅化合物8279，它充当GHSR1A选择性G蛋白偏置激动剂，因此减弱GHSR1A介导的BARR信号传导。初始数据显示8279减少多巴胺转运蛋白敲除（DAT KO）小鼠（超染性的动物模型），但不影响享乐者进食。此应用的目的是描述G蛋白偏置配体的机理 GHSR1A并在阿片类药物滥用的小鼠模型中询问其治疗潜力。中心假设是G蛋白偏见的GHSR1A激动剂减弱了阿片类药物引起的神经塑性和自我给药。 GHSR1A激活后的BARR募集和/或信号传导降低。该假设将通过使用8279或其衍生物作为我们的主要工具化合物追求三个特定目标：1）阐明 GHSR1A偏置信号传导的生化机制，2）确定GHSR1A的影响对神经塑性的信号传导，3）评估GHSR1A信号传导对阿片类药物诱导的行为的影响。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传导进行测试。测定，基于病毒载体在脑组织中神经可塑性的测量和小鼠自我给药。这些研究很重要和新颖，因为它们将对潜力进行彻底的临床前研究利用GHSR1A功能选择性来预防和/或治疗OUD的治疗效用。