Identification of small molecule NPBWR1 agonists

小分子 NPBWR1 激动剂的鉴定

• 批准号: 10726549
• 负责人: Ann M Decker
• 金额: $ 11.38万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10726549
• 关键词: Adverse effects; Affect; Agonist; Analgesics; Biological Assay; Biological Availability; Brain region; Carrageenan; Cell Line; Cells; Chemicals; Clinic; Constipation; Cyclic AMP; Dependence; Diabetes Mellitus; Dimethyl Sulfoxide; Dose; Dryness; Ensure; Evaluation; Formalin; Formalin Tests; G-Protein-Coupled Receptors; Genes; Health; Hyperalgesia; Immune; In Vitro; Inflammatory; Injections; Knockout Mice; Laboratories; Libraries; Ligands; Ligation; Mediating; Metabolic; Modeling; Morphine; NPBWR1 gene; Naloxone; National Institute of Mental Health; Nerve; Neuropathy; Neuropeptides; Nociception; Obesity; Opioid; Opioid Receptor; Opioid agonist; Pain; Pain management; Pathologic; Patients; Peptides; Persons; Pharmaceutical Chemistry; Pharmaceutical Preparations; Powder dose form; Property; Psychotropic Drugs; Public Health; Regulation; Reporting; Research; Role; Sampling; Series; Solubility; Spinal Cord; Structure; System; Testing; Therapeutic; Validation; Vendor; addiction; blood-brain barrier permeabilization; chronic constriction injury; chronic pain; chronic pain management; conditioned place preference; counterscreen; drug candidate; drug discovery; effective therapy; high throughput screening; inflammatory pain; lead optimization; locus ceruleus structure; mechanical allodynia; midbrain central gray substance; neuropeptide B; non-opioid analgesic; novel; pain model; painful neuropathy; peptidomimetics; pharmacologic; programs; release of sequestered calcium ion into cytoplasm; response; scaffold; sciatic nerve; screening program; small molecule; small molecule libraries; synergism; therapeutic candidate; therapy development; tool

Abstract Chronic pain is one of the leading health problems worldwide. Opioids have served as gold standard for treating moderate to severe pain. However, opioids possess serious adverse effects that limit their use in clinics. Therefore there is an unmet need for alternative effective and non-addictive pain treatments. Neuropeptide B/W Receptor 1 (NPBWR1) has emerged as a novel pain target which upon activation can produced analgesic effects on its own or in synergy with opioids. To date, all reported NPBWR1 agonists are peptides or peptidomimetics that do not cross the blood brain barrier, requiring central administration. To facilitate research on this promising target, we propose to perform a high throughput screen of our diverse small molecule library to identify small molecule agonists (Aim 1). We have developed a battery of in vitro functional assays to characterize NPBWR1 ligands including a cAMP, calcium mobilization and TruPath assays. The 384-well cAMP assay has been demonstrated to have good robustness Z'>0.5, S/B > 20. Hits will be validated using counter screen and orthogonal assays. Validated hits will be assessed for ADME profiling and selectivity against other targets (Aim 2). Completion of this proposal will yield small molecule NPBWR1 that serve as starting points for subsequent medicinal chemistry optimization to develop into therapeutics for chronic pain and other NPBWR1-mediated conditions.

抽象的 慢性疼痛是全球主要的健康问题之一。阿片类药物已成为黄金标准 治疗中度至重度疼痛。但是，阿片类药物具有严重的不良影响，限制了它们的使用 诊所。因此，需要替代有效和非添加性疼痛治疗的替代需求。 神经肽B/W受体1（NPBWR1）已成​​为一种新的疼痛靶标，在激活后可以 对其自身或与阿片类药物的协同作用产生镇痛作用。迄今为止，所有报告的NPBWR1激动剂 是不跨越血脑屏障的肽或肽仪，需要中央给药。 为了促进对这个有希望的目标的研究，我们建议对我们的高吞吐量进行高吞吐量 各种小分子文库以鉴定小分子激动剂（AIM 1）。我们已经开发了一个电池 体外功能测定，以表征NPBWR1配体，包括cAMP，钙动员和 Trupath分析。已证明384孔营地测定法具有良好的鲁棒性Z'> 0.5，S/b> 20。命中将使用反屏幕和正交分析进行验证。经过验证的命中将被评估 对其他目标进行分析和选择性（AIM 2）。该提议的完成将产生少量 分子NPBWR1作为后续药物化学优化的起点 进入慢性疼痛和其他NPBWR1介导的疾病的治疗剂。