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: 10212896
• 负责人: Paul W. Czoty
• 金额: $ 50.26万
• 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/10212896
• 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; 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）一直是缺乏广泛有效药物的昂贵公共卫生问题。 拟议的研究的科学前提是，nocceptin/orphanin FQ Pepperede的大脑受体 （NOP）是新药物的有希望的目标，但在复杂的非人类隐私中翻译了研究 （NHP）需要模型来告知和直接药物开发和临床测试。这个前提是基于 鼓励来自啮齿动物模型的数据和使用NHP实验室的正面初步数据 丁丙诺啡及其衍生物BU08028称为“双功能” MOP/NOP激动剂，因为它刺激了 NOP和MU阿片类肽（MOP）受体。拟议的研究结合了一个良好的特征 慢性乙醇（ETOH）饮用，新型NOP和MOP/NOP-ACTING药物的临床相关NHP模型，A 使用正电子发射的药物治疗评估和无创脑成像的翻译方法 断层扫描（宠物成像）。在使用既定程序诱使饮用ETOH之后，男性和女性 恒河猴将可以自由进入EtoH；响应接受食物颗粒也将被监测为 潜在副作用的指数。特定的目标1将确定丁丙诺啡及其衍生物的影响 BU08028，结合有选择性刺激或阻断拖把或NOP接收器的药物。结果将 揭示了MOP和NOP受体刺激对双功能激动剂对功能的相对贡献 降低ETOH饮酒，表明药物的理想药物概况。接下来（目标2），毒品 拥有所需的轮廓将从共同合成的新型化合物目录中选择 研究员斯蒂芬·丈夫博士。候选人将每天管理几个月，并对 中度和大量饮酒（分别每天6或22个小时）将使用翻译确定 P.I.开发的方法我们希望确定一种产生长时间抑制的化合物 ETOH饮用而不改变食物维护的反应或产生不良反应。目标3由 使用与目标1和2平行运行的新型radiotracer [11C] NOP-1A的PET成像研究。这些研究 将表征（1）基本NOP受体可用性对ETOH初始敏感性的影响，（2） （3）有效治疗对NOP受体的影响 可用性，（4）在戒酒期间，NOP受体可用性恢复的程度 重要的是，（5）所有这些措施的性别差异。总之，这些研究的结果将提供新颖 翻译数据以支持开发MOP/NOP和NOP选择激动剂的可行性和效率 作为新型的AUD药物疗法，使用了翻译，临床相关的NHP模型。