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

发现GPR171小分子配体用于治疗慢性疼痛

• 批准号: 10604177
• 负责人: Bingfa Sun
• 金额: $ 29.83万
• 依托单位: CONFOMETRX, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10604177
• 关键词: Adverse effects; Affect; Agonist; Analgesics; Animal Model; Animals; Behavior; Biochemistry; Biological Assay; Central Nervous System; Chemicals; Clinical Trials; Cryoelectron Microscopy; DNA; Dose; Economics; Funding Opportunities; G-Protein-Coupled Receptors; Helping to End Addiction Long-term; Libraries; Ligand Binding; Ligands; Medical; Medicine; Modeling; Nociception; Nociceptors; Opiate Addiction; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pain management; Peripheral; Peripheral Nervous System; Persons; Pharmacology; Phase; Postoperative Pain; Property; Public Health; Reporting; Resolution; Risk; Spinal Ganglia; Structure; Technology; Testing; Tissues; United States; Ventilatory Depression; abuse liability; addiction; chronic pain; chronic pain management; inflammatory pain; midbrain central gray substance; non-opioid analgesic; novel; opioid epidemic; opioid mortality; opioid use; pain reduction; pain signal; painful neuropathy; response; screening; side effect; small molecule; structural biology; therapeutic candidate; therapy development; tool; transmission process; virtual screening

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)”.

项目摘要 慢性疼痛是一种令人衰弱的医疗状况，影响了美国约5000万人。 阿片类药物是中度至重度疼痛的常见药物类别，但并非特别 有效治疗多种类型的慢性疼痛。阿片类药物具有呼吸的潜在致命副作用 抑郁症和长期阿片类药物的使用会导致耐受性和成瘾。这些因素在一起有助于 在美国，严重的阿片类药物危机在 近年来。该提议的目的是为一种新颖 靶标GPR171，用于治疗慢性疼痛。 GPR171是最近去脱磷酸G蛋白偶联的 受体（GPCR），在对疼痛信号传递和调节至关重要的组织中表达，例如 中枢神经系统和外周神经系统中的背根神经节中的周期性灰色。 GPR171的活动调节伤害性神经元的功能，使其成为疼痛的潜在目标 管理。在伤害性疼痛的动物模型中，炎症性疼痛，神经性疼痛和术后 疼痛，GPR171的激活显着减少了疼痛相关行为。没有加强特性 在功能剂量下检测到，证据表明GPR171的外围激活足以BE 简单的。 当前，只有两个小分子配体以GPR171闻名，既有效力都适中 为了充分意识到GPR171成为慢性疼痛治疗的目标，至关重要 发现并开发其他GPR171配体作为工具化合物和治疗候选物。基于我们 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编码的库 筛选和基于结构的虚拟筛选以识别新颖的命中化合物并验证它们 实验。 该提案是对资金机会公告RFA-NS-20-011的回应，标题为“治愈 倡议：开发针对增强疼痛管理的疗法和技术（R43/R44- 不允许临床试验）。