Development of Next-generation Pharmacotherapy for Opioid Use Disorders

摘要： 本申请响应RFA-DA-19-002，提出了快速跟踪IND的分阶段计划 开发治疗阿片使用障碍的下一代药物(OUD)。小分子化合物 建议开发的是针对伤害素阿片受体(NOP)的药物，并显示出良好的前景 自我管理训练的非人灵长类动物(恒河猴)减少羟考酮摄入量的效果 羟考酮的疗效与丁丙诺啡相似。但与丁丙诺啡不同的是，NOP靶向 激动剂先导化合物本身在猴子身上没有增强作用。也不像丁丙诺啡 以及美沙酮，目前用于治疗尿毒症，以NOP为靶标的先导化合物不会产生物理 依赖、耐受或呼吸抑制，取决于重复给药。适用于非医疗机构 处方类阿片成瘾，美沙酮和丁丙诺啡，均被批准为非法阿片(海洛因)成瘾 治疗，都用到了。然而，美沙酮，一种MU阿片受体(MOP)完全激动剂，有严重的滥用 长期使用后停药的责任和原因、对美沙酮诊所的依赖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kappa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，它的效果较差。 在减少药物使用、渴求和复发方面优于美沙酮。针对伤害素/孤儿FQ的激动剂 肽(NOP)受体是第四种阿片受体亚型，调节MOP激动剂和 阿片类药物，特别是在疼痛和奖赏回路中。我们的初步数据显示，小分子NOP 激动剂减少吗啡诱导的啮齿动物奖赏，这在我们的初步数据中得到了进一步证实 非人灵长类动物，展示了一种NOP/MOP部分激动剂在 减少羟考酮的自我给药，不会产生依赖或呼吸抑制。同舟共济 到目前为止，我们的数据表明，NOP激动剂是一种有前途的治疗非法和 处方类阿片使用障碍，并可能提供丁丙诺啡使用的替代方案。 在本项目的UG3阶段，我们建议进行非GLP ADME-TOX和疗效确认， 如果有必要，还可以进行额外的领导优化，目标/里程碑是提名一名 候选人和后备候选人，用于IND使能研究和IND申请(在UH3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).