Buprenorphine analogs for the treatment of opioid abuse

项目摘要 最近类阿片误用和滥用明显增加，类阿片过量死亡率普遍 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遗传学意义的 阿片受体功能和药物作用的适当评价，本提案的目标是建立一个 用于丁丙诺啡类似物的功能谱以改善阿片样物质相关侧的翻译桥 对灵长类动物的影响先前的研究表明，具有混合μ阿片样物质的丁丙诺啡类似物BU 08028 肽（MOP）和痛敏肽/痛敏素FQ肽（NOP）部分激动剂活性是一种安全的镇痛剂， 滥用责任该提案将进一步研究丁丙诺啡激发的功能概况。 化合物BU 08028和BU 14003在调节阿片样物质使用障碍的三个主要方面，即，虐待 责任，复发和身体依赖。该提案包含三个目标：1）区分功能 急性和慢性给药后来自阿片样物质的丁丙诺啡激发化合物的分布。2)到 证明丁丙诺啡激发的化合物减轻滥用相关的功能有效性 包括羟考酮和海洛因在内的阿片类药物的影响。3)证明功能有效性 丁丙诺啡激发的化合物，以减轻阿片类药物依赖的不良反应。这些非- 人类灵长类动物行为测定已经被专门设计来反映 用于抑制阿片类药物相关的滥用倾向和身体依赖性的丁丙诺啡激发的化合物 并评估其功能有效性和选择性。我们独特的一套行为和生理分析， 清醒的、行为正常的非人类灵长类动物，结合新的丁丙诺啡激发的 化合物，为确定阿片类药物诱导的有效药物奠定了突破性的基础。 副作用，并阐明未来的临床干预措施和阿片类药物使用的治疗选择 disorder.

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.