Targeting the allosteric sodium site with novel probes for delta opioid receptor

用新型 δ 阿片受体探针靶向变构钠位点

基本信息

批准号：
10892532
负责人：
Tao Che
金额：
$ 65.31万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-01 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10892532
关键词：
Absence of pain sensation Adenosine Adrenergic Agents Adverse effects Agonist Amino Acids Analgesics Animal Model Animals Arrestins Back Behavioral Binding Binding Proteins Binding Sites Biological Assay Brain Cell Line Cessation of life Charge Clinical Complex Cryoelectron Microscopy Crystallography Dependence Development Dopamine Drug Kinetics Epidemic F2R gene G-Protein-Coupled Receptors GTP-Binding Proteins Generations Goals Human In Vitro Lead Ligand Binding Ligands Longevity Mediating Membrane Membrane Proteins Metabolic Morphinans Motor Activity Movement Mus Mutation Opioid Opioid Analgesics Opioid agonist Pain Pain Disorder Pain management Pathway interactions Patients Penetration Peptide Hydrolases Pharmaceutical Chemistry Pharmaceutical Preparations Pharmacology Pharmacotherapy Physiological Processes Plasma Play Population Property Receptor Activation Resolution Seizures Series Signal Pathway Signal Transduction Site Sodium Structure Structure-Activity Relationship Testing Transfection Ventilatory Depression Water abuse liability addiction addiction liability allodynia analog beta-arrestin chronic constriction injury chronic pain chronic pain management computational chemistry cysteinyl-leukotriene delta opioid receptor design disability efficacious treatment experience health economics in vivo mechanical allodynia motivated behavior mu opioid receptors next generation novel novel strategies opioid epidemic opioid overdose opioid use disorder pain model painful neuropathy pharmacologic pre-clinical prescription opioid prescription opioid misuse protein activation protein complex public health relevance receptor screening side effect socioeconomics sodium ion structural biology therapeutically effective

项目摘要

ABSTRACT Opioid use disorders (OUD) are responsible for a major health and socioeconomic crisis in the US, resulting in more than $500B burden on the economy and 75,673 deaths in the year leading up to April, 2021. More than 80% of OUD cases began with the use of prescription opioid painkillers, which remain in use due to their efficacy in treating severe pain. The current clinically-used analgesics target the mu opioid receptor (MOR), which also produces of liabilities of dependence and addiction leading to OUD, and potentially lethal respiratory depression. Poorly treated pain and diversion and misuse of prescription opioid drugs are key contributors to the worsening opioid epidemic. Development of new safe and effective analgesics with diminished addiction and abuse potential is desperately needed to reduce usage of MOR agonist-based analgesics which promote OUD. We propose to target the sodium site in the delta opioid receptor (DOR) as a novel mechanism to develop pain relievers devoid of the adverse effects associated with MOR agonist analgesics. We propose to use a bitopic ligand strategy, generating novel DOR agonists binding to both the conventional orthosteric site and the sodium site in the DOR. Emerging evidence suggests these novel bitopic DOR ligands produce analgesia but lack the seizure phentotype associated with first generation DOR agonists limited to targeting the orthosteric site of DOR. Our main goal is establish a relationship between DOR efficacy and potency at G-protein and arrestin signaling pathways with binding of the ligands within the sodium site. Our intial bitopic design, C6-quino, is validated by cryoEM structures suggesting that binding in the sodium site leads to partial agonism and a unique functional selectivity away from arrestin pathway signaling over known DOR agonists binding solely to the orthosteric site. To the best of our knowledge, probes with partial agonism at DOR are rare and their effects on DOR-mediated analgesia and other adverse effects are currently not well established. Our current lead has optimal in vitro ADME properties with favorable protein binding and metabolic stability, lacks the typical DOR mediated seizures and other CNS adverse effects while ameliorating allodynia in a neuropathic pain model. Our central hypothesis postulates that targeting the allosteric sodium site in conjunction with the orthostric site by diversification of DOR bitopics guided by cryoEM-enabled SAR approaches will lead to safer analgesics effective against chronic pain. Preliminary evidence suggests probes synthesized will also lack the typical side- effects associated with both DOR as well as clinically used MOR agonists. Using structure based design, we will further optimize our current lead for DOR subtype selectivity (1000x selective), in vitro potency (with DPPDE-like potency of G-protein activation) and in vivo DOR potency (seeking analgesia at ~5-10 mg/kg, s.c. or p.o.) to design our next generation bitopics. Attempts will also be made to enhance brain penetration and CNS activity by swapping the charged guanidino group. These goals will be accomplished by an interdisciplinary team with synergistic experience in medicinal chemistry, computational chemistry, structural biology and pharmacology.

抽象的阿片类药物使用障碍 (OUD) 是造成美国重大健康和社会经济危机的原因，截至 2021 年 4 月的一年中，经济负担超过 $500B，死亡人数为 75,673 人。 80% 的 OUD 病例是从使用处方阿片类止痛药开始的，由于其疗效，这些止痛药仍在使用在治疗剧烈疼痛时。目前临床使用的镇痛药以μ阿片受体（MOR）为靶点，该受体也产生依赖性和成瘾性，导致 OUD 和潜在致命的呼吸抑制。疼痛治疗不当以及处方阿片类药物的转移和滥用是导致病情恶化的关键因素鸦片类药物泛滥。开发新的安全有效的镇痛药，减少成瘾和滥用迫切需要发挥潜力来减少促进 OUD 的 MOR 激动剂镇痛药的使用。我们建议以 δ 阿片受体 (DOR) 中的钠位点作为开发的新机制止痛药没有与 MOR 激动剂镇痛药相关的副作用。我们建议使用一个双位配体策略，生成新型 DOR 激动剂，同时结合常规正位点和 DOR 中的钠位点。新出现的证据表明这些新型双位 DOR 配体可产生镇痛作用，但缺乏与第一代 DOR 激动剂相关的癫痫表型，仅限于靶向正位点的 DOR。我们的主要目标是建立 DOR 功效与 G 蛋白和抑制蛋白的效力之间的关系配体在钠位点内结合的信号传导途径。我们最初的双位设计 C6-quino 是通过冷冻电镜结构验证表明钠位点的结合导致部分激动和独特的功能选择性远离视紫红质抑制蛋白途径信号转导，而已知的 DOR 激动剂仅与正位点。据我们所知，对 DOR 具有部分激动作用的探针很少见，它们对 DOR 的影响 DOR 介导的镇痛和其他不良反应目前尚未明确。我们目前的领先优势是最佳的体外 ADME 特性，具有良好的蛋白质结合和代谢稳定性，缺乏典型的 DOR 介导癫痫发作和其他中枢神经系统不良反应，同时改善神经性疼痛模型中的异常性疼痛。我们的中心假设假设，针对变构钠位点与正位由冷冻电镜 SAR 方法引导的 DOR 双位点多样化将带来更安全的镇痛药对慢性疼痛有效。初步证据表明合成的探针也缺乏典型的副作用与 DOR 以及临床使用的 MOR 激动剂相关的效应。使用基于结构的设计，我们将进一步优化我们目前在 DOR 亚型选择性（1000 倍选择性）、体外效力（与 DPPDE 类似）方面的领先优势 G 蛋白激活的效力）和体内 DOR 效力（寻求约 5-10 mg/kg 的镇痛，皮下或口服）设计我们的下一代双主题。还将尝试增强大脑渗透力和中枢神经系统活动通过交换带电的胍基团。这些目标将由一个跨学科团队来实现药物化学、计算化学、结构生物学和药理学方面的协同经验。