Development of Next-generation Pharmacotherapy for Opioid Use Disorders

摘要： 该申请针对 RFA-DA-19-002 提出了一项分阶段计划，将快速跟踪 IND 开发下一代治疗阿片类药物使用障碍（OUD）的药物。小分子化合物 提议开发的药物针对伤害感受素阿片受体 (NOP)，并已显示出良好的前景 在经过自我给药训练的非人灵长类动物（恒河猴）中减少羟考酮摄入量的功效 羟考酮的功效与丁丙诺啡相似。但与丁丙诺啡不同的是，针对 NOP 的 在猴子中，激动剂先导化合物本身没有表现出增强作用。也不同于丁丙诺啡 和美沙酮，目前用于治疗 OUD，NOP 靶向先导化合物不会产生物理作用 重复给药后产生依赖性、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，均被批准用于治疗非法阿片类药物（海洛因）成瘾 治疗，都用过。然而，美沙酮，一种 mu 阿片受体 (MOP) 完全激动剂，已被严重滥用 长期使用后导致戒断、对美沙酮诊所的依赖以及药物过量的风险 诱发呼吸抑制。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，临床研究表明其效果较差 与美沙酮相比，在减少药物使用、渴望和复发方面效果更好。针对伤害感受肽/孤啡肽 FQ 的激动剂 肽（NOP）受体，第四种阿片受体亚型，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中。我们的初步数据表明，小分子 NOP 激动剂减少啮齿类动物吗啡诱导的奖赏，这在我们的初步数据中得到进一步证实 非人类灵长类动物，展示了 NOP/MOP 部分激动剂的有前途的抗奖励特性 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药物和药物的新方法。 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方案。 在该项目的UG3阶段，我们建议进行non-GLP ADME-tox和功效确认， 如果有必要的话，还可以进行额外的先导优化，目标/里程碑是“IND”的提名 候选者和后备候选者，用于支持 IND 的研究和 IND 备案（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).