Development of cebranopadol, a potent dual MOP/NOP agonist, for the treatment of Opioid Use Disorder (OUD)

摘要/总结 美国正在经历阿片类药物滥用，成瘾和过量的危机;最近一年， 超过100，000例与毒品相关的过量死亡，其中75%涉及阿片类药物。目前的药物治疗 阿片样物质使用障碍（OUD）靶向μ阿片样肽（MOP）受体，其为五类阿片样物质受体之一。 这些疗法包括完全MOP激动剂美沙酮、部分MOP激动剂丁丙诺啡和MOP激动剂美沙酮。 拮抗剂纳洛酮。使用这些药物治疗OUD有几个缺点，包括 滥用的可能性，身体依赖的发展，以及过量的风险，特别是美沙酮和 丁丙诺啡丁丙诺啡和纳洛酮也会引发严重的戒断症状。因此，迫切需要 需要用于治疗OUD的改进的治疗剂。西博帕多（TRN-228）是一种一流的合成药物， 一种因其治疗疼痛的双重作用机制而开发的药物，通过对两者的高亲和力和效力来介导 MOP和FQ受体（NOP）中的痛敏肽/痛敏肽。NOP受体激活与降低的 耐受性、滥用相关行为、成瘾和身体依赖的发展。在此UG3/UH3 Park Therapeutics正在开发TRN-228作为一流的双重MOP/NOP激动剂， 作为一种安全有效的治疗OUD的方法。初步的非临床和临床数据表明， 西博帕多滥用和身体依赖的可能性较低， 与纯MOP激动剂如吗啡和羟考酮相比。TRN-228还能减少吗啡，海洛因， 和可卡因自我给药的大鼠，并没有引起戒断时，给予阿片类药物依赖的大鼠。的 该提案的UG3阶段将测试口服TRN-228是否是一种安全且潜在有效的替代治疗方法 对于OUD，基于以下特定目的：1）确定TRN-228对静脉内芬太尼的影响 在阿片类药物依赖大鼠中自我给药和芬太尼诱导的呼吸抑制，2）测定IV TRN-228的滥用潜力，和3）评估TRN-228抑制戒断的能力。在会见 UG3 Go/No-Go里程碑，Park将进入UH3阶段，以证明治疗疗效 TRN-228在减少阿片类药物使用方面的作用，戒断或滥用的风险较低，这将通过4） 确定TRN-228对阿片类耐受参与者中芬太尼诱导的呼吸抑制的作用， 5)评价TRN-228阻断氢吗啡酮主观效应的能力。这些研究将 通过确定TRN-228的安全性和初步疗效，显著推进该领域。成功 这些目标的完成将指导未来的努力，以建立FDA批准的临床计划。

ABSTRACT/SUMMARY The U.S. is experiencing a crisis of opioid misuse, addiction, and overdose; in the most recent year, there were over 100,000 drug-related overdose deaths, 75% of which involved opioids. Current pharmacotherapies for opioid use disorder (OUD) target mu opioid peptide (MOP) receptors, one of five classes of opioid receptors. These therapies include the full MOP agonist methadone, the partial MOP agonist buprenorphine, and the MOP antagonist naltrexone. There are several drawbacks in using these medications to treat OUD, which include the potential for abuse, development of physical dependence, and risk of overdose, particularly for methadone and buprenorphine. Buprenorphine and naltrexone also trigger severe withdrawal symptoms. There is thus an urgent need for an improved therapeutic for the treatment of OUD. Cebranopadol (TRN-228) is a first-in-class synthetic drug developed for its dual-action mechanism in treating pain, mediated by high affinity and potency for both MOP and nociceptin/orphanin FQ receptor (NOP). NOP receptor activation has been associated with reduced development of tolerance, abuse-related behavior, addiction, and physical dependence. In this UG3/UH3 proposal, Park Therapeutics is developing TRN-228 as a first-in-class dual MOP/NOP agonist that can be used as a safe and effective treatment for OUD. Preliminary nonclinical and clinical data indicate that cebranopadol has low potential for abuse and physical dependence and produces milder respiratory depression compared to pure MOP agonists such as morphine and oxycodone. TRN-228 also decreases morphine, heroin, and cocaine self-administration in rats and did not induce withdrawal when given to opioid-dependent rats. The UG3 phase of this proposal will test whether oral TRN-228 is a safe and potentially effective alternative treatment for OUD, based on the following Specific Aims: 1) determining the effects of TRN-228 on intravenous fentanyl self-administration and fentanyl-induced respiratory depression in opioid-dependent rats, 2) determining the IV abuse potential of TRN-228, and 3) assessing the ability of TRN-228 to suppress withdrawal. Upon meeting the UG3 Go/No-Go milestones, Park will progress to the UH3 phase which will demonstrate the therapeutic efficacy of TRN-228 in decreasing opioid use with low risk of withdrawal or abuse, which will be accomplished by 4) determining the effects of TRN-228 on fentanyl-induced respiratory depression in opioid-tolerant participants and 5) evaluating the ability of TRN-228 to block the subjective effects of hydromorphone. These studies will significantly advance the field by establishing the safety and preliminary efficacy of TRN-228. Successful completion of these aims will guide future efforts to establish a clinical program for FDA approval.