NOP Receptors in nonhuman primate models of AUD

AUD 非人灵长类动物模型中的 NOP 受体

• 批准号: 10386932
• 负责人: Paul W. Czoty
• 金额: $ 49.76万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-10 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10386932
• 关键词: Acute; Adolescent; Adult; Adverse effects; Affect; Agonist; Alcohol abuse; Alcohol consumption; Behavioral; Brain; Brain imaging; Buprenorphine; Catalogs; Chronic; Data; Dose; Ethanol; Female; Food; Heavy Drinking; Hour; Husband; Imaging Techniques; Individual; Laboratories; Long-Term Effects; Macaca mulatta; Measures; Methods; Modeling; Monitor; Monkeys; National Institute on Alcohol Abuse and Alcoholism; ORL1 receptor; Opioid Peptide; Parents; Peptide Receptor; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phenotype; Positron-Emission Tomography; Procedures; Public Health; Recovery; Research; Research Personnel; Rodent Model; Role; Running; Scanning; Sex Differences; Strategic Planning; Testing; Time; TimeLine; alcohol abstinence; alcohol availability; alcohol sensitivity; alcohol use disorder; antagonist; base; chronic alcohol ingestion; clinically relevant; cost; design; drinking; drug development; drug efficacy; efficacious treatment; imaging study; indexing; male; nociceptin; nonhuman primate; novel; novel therapeutics; preclinical study; radiotracer; receptor; research clinical testing; response; side effect; translational approach; translational model; translational study

PROJECT SUMMARY. Alcohol use disorder (AUD) persists as a costly public health problem that lacks widely effective medications. The scientific premise of the proposed research is that brain receptors for the nociceptin/orphanin FQ peptide (NOP) are promising targets for new medications, but translational studies in sophisticated nonhuman primate (NHP) models are needed to inform and direct drug development and clinical testing. This premise is based on encouraging data from rodent models and positive preliminary data from our NHP laboratory using buprenorphine and its derivative BU08028, termed a “bifunctional” MOP/NOP agonist because it stimulates both NOP and mu opioid peptide (MOP) receptors. The proposed studies combine a well-characterized, clinically relevant NHP model of chronic ethanol (EtOH) drinking, novel NOP- and MOP/NOP-acting drugs, a translational method of pharmacotherapy assessment and noninvasive brain imaging using positron emission tomography (PET imaging). After being induced to drink EtOH using established procedures, male and female rhesus monkeys will have free access to EtOH; responding to receive food pellets will also be monitored as an index of potential side effects. Specific Aim 1 will determine the effects of buprenorphine and its derivative BU08028, in combination with drugs that selectively stimulate or block MOP or NOP receptors. The results will reveal the relative contribution of MOP and NOP receptor stimulation to the ability of bifunctional agonists to decrease EtOH drinking, indicating the ideal pharmacological profile for a medication. Next (Aim 2), drugs that possess the desired profile will be selected from among a catalog of novel compounds synthesized by Co- Investigator Dr. Stephen Husbands. Candidates will be administered daily for several months and effects on moderate and heavy drinking (6 or 22 hours per day, respectively) will be determined using a translational approach developed by the P.I. We expect to identify a compound that produces prolonged suppression of EtOH drinking without altering food-maintained responding or producing adverse effects. Aim 3 consists of PET imaging studies using the novel radiotracer [11C]NOP-1A that run parallel to Aims 1 and 2. These studies will characterize (1) the influence of basal NOP receptor availability on initial sensitivity to EtOH, (2) the effects of long-term EtOH drinking on NOP receptors, (3) the effects of efficacious treatments on NOP receptor availability, (4) the extent of recovery of NOP receptor availability during abstinence from EtOH and, importantly, (5) sex differences in all these measures. Together, the results of these studies will provide novel, translational data to support the feasibility and efficacy of developing MOP/NOP and NOP-selective agonists as novel AUD pharmacotherapies using translational, clinically relevant NHP models.

项目摘要。 酒精使用障碍（AUD）一直是一个代价高昂的公共卫生问题，且缺乏广泛有效的药物。 拟议研究的科学前提是伤害感受肽/孤啡肽 FQ 肽的大脑受体 （NOP）是新药的有希望的目标，但在复杂的非人类灵长类动物中进行转化研究 (NHP) 模型需要为药物开发和临床测试提供信息和指导。这个前提是基于 来自啮齿动物模型的令人鼓舞的数据和我们 NHP 实验室使用的积极初步数据 丁丙诺啡及其衍生物 BU08028，被称为“双功能”MOP/NOP 激动剂，因为它刺激 NOP 和 mu 阿片肽 (MOP) 受体。拟议的研究结合了特征良好的、 慢性饮酒 (EtOH) 的临床相关 NHP 模型、新型 NOP 和 MOP/NOP 作用药物、 使用正电子发射进行药物治疗评估和无创脑成像的转化方法 断层扫描（PET 成像）。使用既定程序诱导男性和女性饮用乙醇后 恒河猴将可以免费获得乙醇；对接收食物颗粒的反应也将受到监测 潜在副作用指数。具体目标 1 将确定丁丙诺啡及其衍生物的作用 BU08028，与选择性刺激或阻断 MOP 或 NOP 受体的药物组合。结果将 揭示了 MOP 和 NOP 受体刺激对双功能激动剂能力的相对贡献 减少乙醇饮酒，表明药物的理想药理学特征。接下来（目标 2），药物 具有所需特征的化合物将从Co-合成的新型化合物目录中进行选择 调查员斯蒂芬·哈斯本兹博士。候选人将在几个月内每天接受管理，并对其产生影响 中度和重度饮酒（分别为每天 6 小时或 22 小时）将使用转化来确定 由 P.I. 开发的方法我们希望找到一种能够长时间抑制 饮用乙醇不会改变食物维持的反应或产生不良影响。目标 3 包括 使用新型放射性示踪剂 [11C]NOP-1A 进行 PET 成像研究，与目标 1 和 2 并行。这些研究 将表征 (1) 基础 NOP 受体可用性对 EtOH 初始敏感性的影响，(2) 长期饮用EtOH对NOP受体的影响，（3）有效治疗对NOP受体的影响 可用性，(4) 戒除 EtOH 期间 NOP 受体可用性的恢复程度，以及 重要的是，（5）所有这些措施中的性别差异。总之，这些研究的结果将提供新颖的、 转化数据支持开发 MOP/NOP 和 NOP 选择性激动剂的可行性和有效性 作为使用转化的、临床相关的 NHP 模型的新型 AUD 药物疗法。