NOP Receptors in nonhuman primate models of AUD

项目总结。 酒精使用障碍(AUD)仍然是一个代价高昂的公共健康问题，缺乏广泛有效的药物。 这项拟议研究的科学前提是伤害素/孤儿FQ肽的大脑受体 (NOP)是新药的有希望的靶点，但在复杂的非人类灵长类动物中进行翻译研究 需要(NHP)模型来提供信息并指导药物开发和临床试验。这一前提是基于 来自啮齿动物模型的令人鼓舞的数据和来自我们的NHP实验室的积极的初步数据 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。拟议的研究结合了一种具有良好特点的、 临床相关的慢性酒精(Etoh)饮酒的NHP模型，新的NOP和MOP/NOP作用药物，a 利用正电子发射进行药物治疗评价和无创脑成像的转换方法 体层摄影术(PET成像)。在按照既定程序被引诱饮用乙醇后，男性和女性 恒河猴将可以自由使用乙醇；对收到食物颗粒的反应也将作为 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拖把或NOP受体的药物联合使用。结果将会是 揭示MOP和NOP受体刺激对双功能激动剂 减少乙醇饮用量，表明一种药物的理想药理学特征。下一步(目标2)，药物 具有所需轮廓的化合物将从由Co-C合成的新化合物目录中选择 调查员斯蒂芬·霍班兹博士。候选人将在几个月内每天接受治疗，并对 中度饮酒和重度饮酒(分别为每天6小时或22小时)将使用翻译后的 由私家侦探开发的方法。我们希望能识别出一种化合物，可以产生长期抑制 在不改变食物的情况下饮用乙醇--维持反应或产生不良影响。目标3由以下内容组成 使用新型放射性示踪剂[11C]NOP-1A与AIMS 1和2平行进行的PET成像研究。这些研究 将表征(1)基础NOP受体的可用性对乙醇初始敏感性的影响，(2)影响 长期饮用乙醇对NOP受体的影响；(3)有效治疗对NOP受体的影响 可获得性，(4)乙醇戒断期间NOP受体可获得性的恢复程度， 重要的是，(5)所有这些指标的性别差异。总而言之，这些研究的结果将提供新的、 翻译数据支持开发MOP/NOP和NOP选择性激动剂的可行性和有效性 作为使用翻译的、临床相关的NHP模型的AUD药物治疗的新方法。

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.