Development of Next-generation Pharmacotherapy for Opioid Use Disorders

摘要： 本申请是对RFA-DA-19-002的回应，提出了一项分阶段计划，将快速跟踪IND 开发下一代阿片类药物使用障碍（OUD）药物。小分子化合物 拟用于开发的靶向痛敏素阿片受体（NOP）， 在接受自我给药训练的非人灵长类动物（恒河猴）中减少羟考酮摄入的功效 羟考酮的功效与丁丙诺啡相似。但与丁丙诺啡不同， 激动剂先导化合物本身在猴子中没有显示出增强作用。与丁丙诺啡不同的是 和美沙酮，目前用于治疗OUD，NOP靶向的铅化合物不产生物理 依赖性、耐受性或呼吸抑制。对于非医疗 处方阿片类药物成瘾，美沙酮和丁丙诺啡，均被批准用于非法阿片类药物（海洛因）成瘾 治疗，使用。然而，美沙酮，μ阿片受体（MOP）完全激动剂，有显着的滥用 长期使用后的责任和原因戒断，依赖美沙酮诊所，以及药物过量的风险- 引起呼吸抑制。丁丙诺啡（Bup），MOP部分激动剂和κ阿片受体（KOP） 拮抗剂，产生有限的呼吸抑制;然而，临床研究表明， 比美沙酮在减少吸毒、毒瘾和复吸方面更有效。靶向FQ中的痛敏肽/阿片肽的激动剂 肽（NOP）受体，第四类阿片受体亚型，调节MOP激动剂的药理学， 阿片类药物，特别是在疼痛和奖励回路。我们的初步数据表明，小分子NOP 激动剂减少吗啡诱导的啮齿类动物的奖励，这在我们的初步数据中得到进一步证实， 在非人灵长类动物中，证明了NOP/MOP部分激动剂在 减少羟考酮自我给药，而不产生依赖性或呼吸抑制。一起 迄今为止，我们的数据表明，NOP激动剂是一种有前途的治疗非法和 处方阿片类药物使用障碍，并可能提供丁丙诺啡使用的替代品。 在本项目的UG 3阶段，我们拟进行非GLP ADME-tox和疗效确认， 以及必要时的额外潜在客户优化，目标/里程碑是“IND”的提名 候选人和后备候选人，用于IND使能研究和IND申报（UH 3阶段）。

ABSTRACT: This application in response to RFA-DA-19-002 proposes a phased plan that will fast track the IND development of a next-generation medication for opioid use disorders (OUD). The small-molecule compounds proposed for development are targeted to the nociceptin opioid receptor (NOP) and have shown promising efficacy in reducing oxycodone intake in nonhuman primates (rhesus monkeys) trained to self-administer oxycodone with efficacies similar to that of buprenorphine. But unlike buprenorphine, the NOP-targeted agonist lead compounds show no reinforcing effects by themselves, in monkeys. Also unlike buprenorphine and methadone, currently used for treating OUDs, NOP-targeted lead compounds do not produce physical dependence, tolerance, or respiratory depression, upon repeated administration. For the non-medical prescription opioid addiction, methadone and buprenorphine, both approved for illicit opioid (heroin) addiction treatment, are used. However, methadone, a mu opioid receptor (MOP) full agonist has significant abuse liability and causes withdrawal after chronic use, reliance on methadone clinics, and risk of drug overdose- induced respiratory depression. Buprenorphine (Bup), a MOP partial agonist and kappa opioid receptor (KOP) antagonist, produces limited respiratory depression; however, clinical studies indicate that it is less effective than methadone in reducing drug use, craving and relapse. Agonists targeted to the nociceptin/orphanin FQ peptide (NOP) receptor, the fourth opioid receptor subtype, modulate the pharmacology of MOP agonists and opioids, particularly in pain and reward circuitries. Our preliminary data shows that small-molecule NOP agonists reduce morphine-induced reward in rodents and this is further confirmed in our preliminary data in nonhuman primates, demonstrating promising anti-rewarding properties of a NOP/MOP partial agonist in decreasing oxycodone self-administration without producing dependence or respiratory depression. Together our data thus far suggests that the NOP agonists are a promising new approach to treat illicit and prescription opioid use disorders and may offer an alternative to buprenorphine use. In the UG3 phase of this project, we propose to conduct non-GLP ADME-tox and efficacy confirmation, and additional lead optimization if warranted, with the goal/milestone being the nomination of a `IND candidate' and backup candidates, for IND-enabling studies and an IND filing (in the UH3phase).