Neuropeptide FF Receptor Antagonists for Pain Treatment

摘要 疼痛是困扰全球数百万人的众多临床疾病的一种症状。系统性 使用阿片类镇痛剂仍然是治疗许多严重疼痛的最有效的方法。这 一类止痛药通常与副作用的发展有关，包括痛觉过敏、耐受性 和依赖性，所有这些都严重限制了它们在疼痛控制方面的有效性。一种前景看好的作战战略 这些问题就是开发阿片类药物的佐剂，旨在提高阿片类药物的疗效，减少阿片类药物的使用 不好的影响。内源性神经肽FF(NPFF)是RF-酰胺类多肽家族的一员， 与两个不同的G蛋白偶联受体NPFFR1和NPFFR2相互作用。新出现的证据表明 NPFFR1拮抗剂可减轻痛觉过敏和对阿片类药物的耐受性，这两种主要副作用会阻碍 阿片类药物在疼痛治疗中的应用。已报道的NPFFR配体大多是多肽或具有 胍的官能团往往对中枢神经系统渗透性差，不适合全身给药。 认识到开发有效和类似药物的小分子NPFFR1拮抗剂的需求尚未得到满足，我们有 进行了高通量筛选活动，并确定一种新的脯氨酸衍生物是一种有希望的热门产品。 初步的构效关系研究已经改善了这些化合物的效力。在这 为进一步优化该支架的应用，我们建议进一步优化该支架，以提高其效价、选择性和类药物性质。

Abstract Pain is a symptom of numerous clinical disorders that afflicts millions of people worldwide. Systemic administration of opioid analgesics remains the most effective treatment for many severe pain conditions. This class of analgesics is often associated with the development of side effects including hyperalgesia, tolerance and dependence, all of which severely limit their effectiveness in pain control. A promising strategy to combat these problems is to develop adjuvants of opioids aimed at increasing opioid efficacy and reducing opioid untoward effects. The endogenous neuropeptide FF (NPFF), a member of the RF-amide family of peptides, interacts with two distinct G protein-coupled receptors, NPFFR1 and NPFFR2. Emerging evidence indicates that NPFFR1 antagonism attenuates hyperalgesia and tolerance to opioids, two major side effects which hinder the use of opioids in pain management. Most of reported NPFFR ligands are peptides or peptidomimetics with a guanidine functional group which often has poor CNS penetration, thus not suitable for systemic administration. Recognizing the unmet need to develop potent and drug-like small molecule NPFFR1 antagonists, we have conducted a high throughput screening campaign and identified a novel proline derivative as a promising hit. Preliminary structure-activity relationship studies have improved the potencies of these compounds. In this application, we propose to further optimize this proline scaffold to improve potency, selectivity and drug-likeness.