Development of Next-generation Pharmacotherapy for Opioid Use Disorders

开发治疗阿片类药物使用障碍的下一代药物疗法

基本信息

批准号：
10680546
负责人：
Nurulain T Zaveri
金额：
$ 218.35万
依托单位：
ASTRAEA THERAPEUTICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-01-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10680546
关键词：
Address Agonist Alcohols Analgesics Analytical Chemistry Attenuated Biological Assay Buprenorphine Chemicals Chronic Clinical Clinical Research Cocaine Cyclic GMP Data Dependence Development Documentation Dose Drug usage Evaluation Formulation Goals Heroin In Vitro Intake Intellectual Property Laboratories Lead Ligands Lymphoma Macaca mulatta Methadone Micronucleus Tests Monkeys Morphine Mus ORL1 receptor Opioid Opioid Antagonist Opioid Receptor Opioid agonist Oral Overdose Oxycodone Pain Peptide Receptor Pharmaceutical Preparations Pharmacology Pharmacotherapy Phase Phase I Clinical Trials Physical Dependence Preparation Process Property Recovery Relapse Rewards Risk Rodent Safety Secure Self Administration Series Telemetry Toxic effect Toxicokinetics Toxicology Training Validation Ventilatory Depression Withdrawal Withdrawal Symptom abuse liability addiction chronic pain craving design drug candidate illicit opioid in vivo kappa opioid receptors lead candidate lead optimization medication for opioid use disorder meetings methadone clinic/center method development mu opioid receptors next generation nociceptin nonhuman primate novel novel strategies opioid epidemic opioid use disorder pre-clinical preclinical development prescription opioid prescription opioid addiction response reward circuitry safety study scaffold scale up small molecule

项目摘要

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).

抽象的：该应用程序响应RFA-DA-19-002提出了一个分阶段计划，该计划将快速跟踪IND 开发用于阿片类药物使用障碍的下一代药物（OUD）。小分子化合物提出的发育针对诺氏蛋白质治疗受体（NOP），并显示出很有希望的在非人类灵长类动物（恒河猴）中减少羟考酮摄入的功效羟考酮的疗效类似于丁丙诺啡。但是与丁丙诺啡不同，nop靶向激动剂铅化合物在猴子中没有表现出自己的增强作用。也与丁丙诺啡不同美沙酮，目前用于治疗Ouds，NOP靶向的铅化合物不会产生物理反复给药后的依赖性，耐受性或呼吸道抑郁症。对于非医学处方阿片类药物成瘾，美沙酮和丁丙诺啡，均批准非法阿片类药物（海洛因）成瘾处理，使用。但是，美沙酮，mu阿片受体（MOP）全部激动剂有重大滥用长期使用后的责任和导致戒断，依赖美沙酮诊所以及药物过量的风险诱发呼吸抑郁症。丁丙诺啡（bup），拖把部分激动剂和卡帕阿片受体（KOP）对手，产生有限的呼吸抑郁症；但是，临床研究表明它的效率较低比美沙酮减少药物使用，渴望和复发。针对Nociteptin/Orphanin FQ的激动剂肽（NOP）受体，第四个阿片受体亚型，调节MOP激动剂的药理学和阿片类药物，特别是在疼痛和奖励电路中。我们的初步数据表明小分子NOP 激动剂减少了吗啡引起的啮齿动物的奖励，这在我们的初步数据中得到了进一步的证实非人类灵长类动物，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郁症。一起到目前为止，我们的数据表明，NOP激动剂是一种有希望的新方法来治疗非法和处方阿片类药物使用障碍，可能会提供丁丙诺啡使用的替代方法。在该项目的UG3阶段，我们建议进行非GLP ADME-TOX和功效确认，如果有必要，则其他潜在客户优化，目标/里程碑是提名候选人和备份候选人，用于辅助研究和IND归档（在UH3相）。