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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.

摘要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，在截至2021年4月的一年中，经济负担超过5000亿美元，死亡人数为75，673人。超过 80%的OUD病例开始使用处方阿片类止痛药，由于其疗效，这些止痛药仍在使用治疗严重的疼痛。目前临床上使用的镇痛剂靶向μ阿片受体（莫尔），其也产生依赖和成瘾的倾向，导致OUD和潜在致命的呼吸抑制。治疗不良的疼痛和处方阿片类药物的转移和滥用是恶化的关键因素阿片类药物流行病开发新的安全有效的镇痛药，减少成瘾和滥用迫切需要减少促进OUD的基于莫尔激动剂的镇痛剂的使用的潜力。我们建议靶向δ阿片受体（DOR）中的钠位点，作为一种新的机制，没有与莫尔激动剂镇痛剂相关的副作用的止痛药。我们建议使用双位配体策略，产生与常规正构位点和配体结合的新型DOR激动剂。 DOR中的钠位点。新出现的证据表明，这些新的双特异性DOR配体产生镇痛作用，缺乏与第一代DOR激动剂相关的癫痫发作表型，仅限于靶向正构位点的DOR。我们的主要目标是建立DOR功效与G蛋白和抑制蛋白效力之间的关系信号传导途径与钠位点内的配体结合。我们最初的双拓扑设计，C6-quino，通过cryoEM结构验证，表明钠位点的结合导致部分激动作用和独特的相对于仅结合抑制蛋白的已知DOR激动剂，正构位点据我们所知，在DOR处具有部分激动作用的探针是罕见的，并且它们对 DOR介导的镇痛和其他不良反应目前尚未得到很好的证实。我们现在的线索最佳的体外ADME特性，具有良好的蛋白结合和代谢稳定性，缺乏典型的DOR 介导的癫痫发作和其他CNS副作用，同时改善神经性疼痛模型中的异常性疼痛。我们的中心假设假定，靶向变构钠位点与正腹肌张力相关，由cryoEM使能SAR方法引导的DOR bitopics多样化的站点将导致更安全的镇痛剂对慢性疼痛有效。初步证据表明，合成的探针也缺乏典型的一面- 与DOR以及临床使用的莫尔激动剂相关的作用。使用基于结构的设计，我们将进一步优化我们目前的DOR亚型选择性（1000倍选择性），体外效力（与DPPDE样 G蛋白活化效力）和体内DOR效力（在约5-10 mg/kg，s.c.或p.o.）到设计我们的下一代双色调。还将尝试增强大脑渗透和中枢神经系统活动通过交换带电荷的胍基。这些目标将由一个跨学科的团队完成，在药物化学、计算化学、结构生物学和药理学方面的协同经验。