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

项目摘要 慢性疼痛是一种使人衰弱的疾病，在美国影响着大约5000万人。 阿片类药物是用于中度至重度疼痛的常见处方类药物，但它们并不特别适合于治疗疼痛。 有效治疗多种慢性疼痛。阿片类药物具有潜在的致命性呼吸道副作用 长期使用阿片类药物会导致耐受和成瘾。这些因素共同促成了 在美国，严重的阿片类药物危机导致每年超过75，000例阿片类药物过量死亡， 近年该提案的目的是开发新的非阿片类候选化合物，用于新的药物治疗。 靶点GPR 171，用于治疗慢性疼痛。GPR 171是一种最近去乙酰化的G蛋白偶联蛋白， 受体（GPCR），并在对疼痛信号传递和调节至关重要的组织中表达，如 中枢神经系统的导水管周围灰质和周围神经系统的背根神经节。 GPR 171的活性调节伤害性神经元的功能，使其成为疼痛的潜在靶点 管理在伤害性疼痛、炎性疼痛、神经性疼痛和术后疼痛的动物模型中， 在疼痛时，GPR 171的激活显著减少疼痛相关行为。没有增强性能， 在功能剂量下检测到，有证据表明GPR 171的外周激活足以 灵验。 目前，只有两种已知的GPR 171小分子配体，两者都具有适度的效力， 功效为了充分实现GPR 171成为慢性疼痛治疗靶点的潜力， 发现并开发其他GPR 171配体作为工具化合物和治疗候选物。基于我们 基于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编码文库 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 实验性的 本提案是对题为“HEAL”的资助机会公告RFA-NS-20-011的回应 倡议：针对增强疼痛管理的治疗和技术开发（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)”.