Discovery of GPR171 small molecule ligands for the treatment of chronic pain

项目摘要 慢性疼痛是一种令人虚弱的疾病，在美国大约有5000万人受到影响。 阿片类药物是治疗中度到重度疼痛的常见处方药类别，但它们并不特别 有效治疗多种慢性疼痛。阿片类药物具有潜在的致命呼吸道副作用 抑郁和长期使用阿片类药物会导致耐受性和成瘾。这些因素加在一起，有助于 美国发生重大阿片类药物危机，导致每年超过7.5万人死于阿片类药物过量 最近几年。这项提议的目的是开发新的、非阿片类候选化合物来开发一种新的 治疗慢性疼痛的靶GPR171。GPR171是最近去孤儿的G蛋白偶联蛋白 受体(GPCR)，并在疼痛信号传递和调制的关键组织中表达，如 中脑导水管周围灰质分布于中枢神经系统，背根神经节分布于周围神经系统。 GPR171的S活动调节伤害性神经元的功能，使其成为疼痛的潜在靶点 管理层。在伤害性疼痛、炎症性疼痛、神经病理性疼痛和术后的动物模型中 疼痛，GPR171的激活显著减少了疼痛相关行为。没有增强性能 在功能剂量下检测到，证据表明GPR171的外周激活足以 很有效。 目前，只有两个已知的小分子配体GPR171，两者都具有适度的效力和 功效。要充分实现GPR171成为慢性疼痛治疗靶点的潜力，关键是 发现和开发更多的GPR171配体作为工具化合物和候选治疗药物。基于我们的 在GPCR生物化学、结构生物学和药理学方面的专业知识，我们建议使用DNA编码库 筛选和基于结构的虚拟筛选以识别新的命中化合物并验证它们 试验性的。 这项提议是对RFA-NS-20-011号文件《融资机会》的回应 倡议：开发旨在加强疼痛管理的疗法和技术(R43/R44- 不允许进行临床试验)“。

Project Summary Chronic pain is a debilitating medical condition, affecting roughly 50 million people in the United States. Opioids are the common prescribed class of medicine for moderate to severe pain, but they are not particularly effective in treating many types of chronic pain. Opioids have potentially fatal side effect of respiratory depression, and long-term opioid usage leads to tolerance and addiction. Together, these factors contribute to significant opioid crisis in the United States, causing more than 75,000 annual opioids overdose deaths in recent years. The purpose of this proposal is to develop novel, non-opioid candidate compounds for a novel target, GPR171, for the treatment of chronic pain. GPR171 is a recently deorphanized G protein-coupled receptor (GPCR) and is expressed in tissues critical for pain signal transmission and modulation, such as periaqueductal gray in central nervous system and dorsal root ganglion in peripheral nervous system. GPR171’s activity regulates the function of nociceptive neurons, making it a potential target for pain management. In animal models for nociceptive pain, inflammatory pain, neuropathic pain and postoperative pain, activation of GPR171 significantly reduced pain related behaviors. No reinforcing properties were detected at functional dose, and evidences suggest that peripheral activation of GPR171 is sufficient to be efficacious. Currently, there are only two small molecule ligands known for GPR171, both with modest potency and efficacy. To fully realize the potential for GPR171 to be a target for chronic pain treatment, it is critical to discover and develop additional GPR171 ligands as tool compounds and therapeutic candidates. Based on our expertise in GPCR biochemistry, structural biology and pharmacology, we propose to use DNA-encoded library screening and structure-based virtual screening to identify novel hit compounds and verify them experimentally. This proposal is in response to funding opportunity announcement RFA-NS-20-011, entitled “HEAL INITIATIVE: Development of Therapies and Technologies Directed at Enhanced Pain Management (R43/R44 - Clinical Trial Not Allowed)”.