The development of delta opioid receptor agonists for the treatment of opioid withdrawal associated behaviors

用于治疗阿片戒断相关行为的 δ 阿片受体激动剂的开发

• 批准号: 10730457
• 负责人: Amynah Amir Ali Pradhan
• 金额: $ 231.69万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10730457
• 关键词: development; delta; opioid; receptor; agonists

Project Summary Chronic opioid use can lead to opioid induced hyperalgesia (OIH), which is a paradoxical increase in pain sensitivity. Currently, the only specific treatment for OIH is opioid cessation. However, during this abstinence period, patients suffer from their untreated pain as well as opioid withdrawal; and the majority of patients relapse within the first year. As a result, OIH patients are particularly vulnerable to the development of opioid use disorder. Novel targeted therapies that could alleviate OIH would result in decreased prescription opioid misuse and abuse. The Pradhan lab has recently shown that δ opioid receptor (δOR) agonists can reduce OIH in a mouse model. However, the development of δOR agonists has been limited by seizurogenic activity and tolerance. These adverse effects appear to be ligand biased, and δOR agonists which favor G protein signaling over β-arrestin recruitment have a reduced propensity to induce analgesic tolerance and pro-convulsant effects. PharmNovo has developed novel G protein biased δOR agonists. Their lead compound, PN6047, is pre-clinically safe and effective in animal models of chronic pain; does not produce convulsions and, shows little analgesic tolerance. The objective of this proposal is to form an academic-industry collaboration to evaluate novel biased δOR agonists for the treatment of OIH. In the UG3 phase, the Pradhan lab will test PN6047 and another lead compound, PN6041 which has higher G-protein bias, in their models of OIH. Dr. Jutkiewicz will test these lead agonists for adverse effects in models of seizurogenic activity and abuse liability. In parallel, PharmNovo will use the two lead compounds to design and synthesize a limited catalogue of novel ligands with the aim to obtain the optimal properties of high selectivity and potency, G protein bias, and good CNS penetrance. These compounds will be screened in vitro by the Kelly Lab. The critical Go/No-Go milestone necessary to progress to the UH3 phase will be the identification of at least one lead compound that is effective in models of OIH, is non-seizurogenic, lacks abuse liability, and has a promising ADME/ toxicity profile; and if we produce at least 10 follow up agonists with high selectivity and differential bias/efficacy. In the UH3 phase, approximately 12-15 compounds identified in the UG3 phase will be fully characterized in cellular and brain membrane assays, with 6-10 of these tested for efficacy in OIH models, for analgesic tolerance, potential development of opioid-induced hyperalgesia, seizurogenic activity, and abuse potential. The most promising compounds will undergo commercial in silico and in vitro ADME/PK and pre-regulatory toxicology testing. Finally, we expect that an emergent lead compound will be suitable for in vivo acute toxicology, dose range finding/maximum tolerated dose testing and, if possible within timescale and budget, repeated dose toxicity studies. If fully successful, the project will have generated a novel, optimized δOR agonist ready to enter Regulatory Toxicology, as a prelude for human testing as a treatment for OIH.

项目概要 长期使用阿片类药物会导致阿片类药物引起的痛觉过敏 (OIH)，这是一种矛盾的疼痛增加 目前，OIH 的唯一具体治疗方法是戒除阿片类药物。 在此期间，患者会遭受未经治疗的疼痛以及阿片类药物戒断，并且大多数患者会复发； 因此，OIH 患者在第一年内特别容易受到阿片类药物使用的影响。 可以缓解 OIH 的新型靶向疗法将减少处方阿片类药物的滥用。 Pradhan 实验室最近表明 δ 阿片受体 (δOR) 激动剂可以减少小鼠的 OIH。 然而，δOR 激动剂的发展受到癫痫活性和耐受性的限制。 不良反应似乎是配体偏向的，δOR 激动剂比 β-arrestin 有利于 G 蛋白信号传导 PharmNovo 具有降低诱导镇痛耐受和促惊厥作用的倾向。 开发了新型 G 蛋白偏向 δOR 激动剂，其先导化合物 PN6047 具有临床前安全性和有效性。 在慢性疼痛的动物模型中；不产生抽搐，并且显示出很少的镇痛耐受性。 该提案的目标是形成学术界合作来评估新型偏向 δOR 激动剂 在 UG3 阶段，Pradhan 实验室将测试 PN6047 和另一种先导化合物， PN6041 具有较高的 G 蛋白偏差，Jutkiewicz 博士将在他们的 OIH 模型中测试这些先导激动剂。 同时，PharmNovo 将使用这两种先导药物。 化合物来设计和合成有限的新型配体目录，目的是获得最佳配体 这些化合物具有高选择性和效力、G 蛋白偏向性和良好的 CNS 渗透性等特性。 由 Kelly 实验室进行体外筛选 进入 UH3 阶段所需的关键的 Go/No-Go 里程碑将是 鉴定出至少一种在 OIH 模型中有效、不致癫痫、缺乏 滥用倾向，并且具有良好的 ADME/毒性特征；并且如果我们生产至少 10 种后续激动剂 在 UH3 阶段，鉴定出大约 12-15 种化合物。 UG3 相将在细胞和脑膜测定中得到全面表征，其中 6-10 个进行了测试 OIH 模型中的功效、镇痛耐受性、阿片类药物引起的痛觉过敏的潜在发展、 最有前途的化合物将在计算机模拟和商业化应用中发挥作用。 最后，我们期望出现一种新的先导化合物。 将适用于体内急性毒理学、剂量范围寻找/最大耐受剂量测试，如果可能的话 在时间范围和预算范围内，重复剂量毒性研究如果完全成功，该项目将产生一个结果。 新型、优化的 δOR 激动剂已准备好进入监管毒理学领域，作为治疗方法进行人体测试的前奏 对于 OIH。