Identification of small molecule NPBWR1 agonists

摘要 慢性疼痛是全球主要的健康问题之一。阿片类药物一直是 治疗中度至重度疼痛。然而，阿片类药物具有严重的不良影响，限制了其在 诊所。因此，对替代、有效和非成瘾性疼痛治疗的需求尚未得到满足。 神经肽B/W受体1(NPBWR1)已成为一种新的疼痛靶点，激活后可 可单独或与阿片类药物协同产生止痛作用。到目前为止，所有报道的NPBWR1激动剂 是不能通过血脑屏障的多肽或多肽类药物，需要中央给药。 为了促进对这一有希望的目标的研究，我们建议对我们的 鉴定小分子激动剂的多样化小分子文库(目标1)。我们已经开发出一种电池 NPBWR1配体的体外功能分析，包括cAMP，钙动员和 TruPath检测。384井cAMP分析已被证明具有良好的稳健性，Z‘&gt；0.5，S/B&gt； 20.将使用计数器筛选和正交分析来验证命中率。将评估经过验证的命中率 ADME概况和对其他目标的选择性(目标2)。完成这项提议将产生很小的收益 作为后续药物化学优化开发起点的NPBWR1分子 用于治疗慢性疼痛和其他由NPBWR1介导的疾病。

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.