Buprenorphine analogs for the treatment of opioid abuse

项目总结 最近阿片类药物滥用和滥用显着增加以及阿片类药物过量死亡的流行 极大地影响了我们的社会。鉴于非人类灵长类动物模型提供了最具亲缘关系的 适当评估阿片受体功能和药物效应，这项建议的目标是建立一个 丁丙诺啡类似物改善阿片类药物相关侧功能的翻译桥 对灵长类动物的影响。以往的研究表明，丁丙诺啡类似物BU08028与Mu阿片混合 多肽(MOP)和伤害素/孤啡肽(NOP)部分激动剂活性是一种安全的止痛药。 滥用责任。该提案将进一步研究丁丙诺啡激发的功能图谱 化合物BU08028和BU14003在调节阿片使用障碍的三个主要方面，即滥用 责任、旧病复发和身体依赖。该提案包含三个目标：1)区分功能 急性和慢性给药后阿片类药物中丁丙诺啡激发的化合物的概况。2)至 展示丁丙诺啡激发的化合物对减轻与滥用有关的功能的有效性 包括羟考酮和海洛因在内的阿片类药物的影响。3)展示功能有效性 丁丙诺啡激发的化合物，以减轻阿片依赖的不良影响。这些非- 人类灵长类动物的行为分析已经被专门设计来反映出 丁丙诺啡激发的化合物抑制阿片类药物相关的滥用倾向和身体依赖 并对其功能效果和选择性进行评价。我们独特的一套行为和生理测试 清醒的，行为非人类的灵长类动物，结合丁丙诺啡启发的新药物的可用性 化合物，为鉴定治疗阿片类药物的有效药物奠定了突破性的基础 不良反应和阿片类药物使用的未来临床干预和治疗选择 无序。

PROJECT SUMMARY The recent marked increase in misuse and abuse of opioids and the epidemic of opioid overdose mortality have greatly affected our society. Given that non-human primate models offer the most phylogenetically appropriate evaluation of opioid receptor functions and drug effects, the goal of this proposal is to establish a translational bridge for the functional profiles of buprenorphine analogs to ameliorate opioid-assoicated side effects in primates. Previous studies demonstrate that a buprenorphine analog BU08028 with mixed mu opioid peptide (MOP) and nociceptin/orphanin FQ peptide (NOP) partial agonist activities is a safe analgesic without abuse liablity. The proposal will further investigate the funcitional profiles of buprenorphine-inspired compounds, BU08028 and BU14003, in modulating three major aspects of opioid use disorder, i.e., abuse liability, relapse, and physical dependence. The proposal contains three aims: 1) To distinguish the functional profiles of buprenorphine-inspired compounds from opioids following acute and chronic administration. 2) To demonstrate the functional effectiveness of buprenorphine-inspired compounds to attenuate the abuse-related effects of opioids including oxycodone and heroin. 3) To demonstrate the functional effectiveness of buprenorphine-inspired compounds to alleviate the adverse effects from opioid dependence. These non- human primate behavioral assays have been designed specifically to reflect the therapeutic potential of buprenorphine-inspired compounds for inhibiting opioid-assoicated abuse liability and physical dependence and assess its functional effecitvenss and selectivity. Our unique set of behavioral and physiological assays in awake, behaving non-human primates, in combination with the availability of novel buprenorphine-inspired compounds, sets the breakthrough stage for the identification of an effective medication for opioid-induced adverse effects and sheds light on future clinical interventions and the treatment options for opioid use disorder.