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

项目摘要 长期使用阿片类药物可导致阿片类药物诱发的痛觉过敏（OIH），这是一种矛盾的疼痛增加 灵敏度目前，OIH的唯一具体治疗方法是阿片类药物戒断。然而，在禁欲期间， 期间，患者遭受未经治疗的疼痛以及阿片类药物戒断;大多数患者复发 在第一年内。因此，OIH患者特别容易受到阿片类药物使用的影响 disorder.可以缓解OIH的新型靶向治疗将减少处方阿片类药物滥用 和虐待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 模型然而，δOR激动剂的发展受到致瘤活性和耐受性的限制。这些 副作用似乎是配体偏向性的，δOR激动剂比β-抑制蛋白更有利于G蛋白信号传导 募集具有降低的诱导镇痛耐受性和促惊厥作用的倾向。PharmNovo拥有 开发了新的G蛋白偏向δOR激动剂。他们的先导化合物PN 6047在临床前安全有效 在慢性疼痛的动物模型中;不产生抽搐，并且几乎不显示镇痛剂耐受性。的 该提案的目的是形成学术-工业合作，以评估新型偏倚δOR激动剂 用于治疗OIH。在UG 3阶段，Pradhan实验室将测试PN 6047和另一种先导化合物， PN 6041在OIH模型中具有更高的G蛋白偏倚。Jutkiewicz医生会测试这些铅激动剂 在致瘤活性和滥用倾向模型中的不良影响。与此同时，PharmNovo将使用两个领先的 化合物设计和合成一个有限的目录的新的配体，目的是获得最佳的 具有高选择性、高效价、G蛋白偏向性和良好的中枢神经系统特异性。这些化合物将 由凯利实验室进行体外筛选。进入UH 3阶段所需的关键通/不通里程碑将 确定至少一种在OIH模型中有效的先导化合物，非致神经性，缺乏 滥用倾向，并具有良好的ADME/毒性特征;如果我们生产至少10种后续激动剂， 高选择性和差异偏倚/功效。在UH 3阶段，在2000年鉴定了大约12-15种化合物。 UG 3阶段将在细胞和脑膜分析中得到充分表征，其中6-10个将进行测试， 在OIH模型中的疗效，镇痛耐受性，阿片类药物诱导的痛觉过敏的潜在发展， 致瘤活性和滥用潜力。最有前途的化合物将在计算机上进行商业化， 体外ADME/PK和监管前毒理学试验。最后，我们希望一种新的先导化合物 适用于体内急性毒理学、剂量范围探索/最大耐受剂量试验，如果可能， 在时间表和预算范围内进行重复给药毒性研究。如果完全成功，该项目将产生 一种新型的、优化的δOR激动剂准备进入监管毒理学，作为人体试验的前奏。 对于OIH。

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.