Small Molecule Probes of the Neuropeptide S Receptor

描述（由申请人提供）：基因技术的重大进步极大地促进了我们发现新型生物系统的能力。尽管这一进展继续以快速的速度进行，但由于缺乏适当的药理学工具，有时会阻碍对新发现系统的全面了解。因此，我们在R01应用中的重点是开发必要的药理学工具，以充分研究最近发现的神经肽S受体的体内功能。神经肽S （NPS）是一种由20个氨基酸组成的肽，通过其同源的g蛋白偶联受体与多种疾病状态有关，包括焦虑、发作性睡病、哮喘、肥胖和潜在的创伤后应激障碍。目前，对非肽NPS分子探针，特别是激动剂的需求显著未满足。用有效和选择性的配体填补这一空白将加速发现作用于NPS受体系统的潜在疗法。此外，与多肽不同，小有机分子更有可能具有全身生物利用性，并能穿透血脑屏障。该申请的具体目标是基于R21“识别神经肽S受体小分子”提案第一年获得的初步数据。虽然在鉴定核心支架和描绘粗略的NPS拮抗剂药效团方面取得了重大进展，但仍有许多开发工作有待完成。首先，没有已知的具有NPS受体功能的小分子激动剂探针。这是很重要的，因为从内源性肽的体外注射中获得的越来越多的证据支持激动剂结构可能比拮抗剂具有更多相关疾病靶点的观点。其次，从类似药物的角度来看，最有希望的拮抗剂先导物对至少一种NPS亚型（主要是107N）具有中等效力。目前的申请建议根据我们的早期线索继续合成和测试新的NPS类似物。这种方法将提供更多类似药物的NPS受体功能小分子探针，并可能最终导致能够治疗焦虑、发作性睡病、哮喘、肥胖或创伤后应激障碍的药物疗法。

DESCRIPTION (provided by applicant): Significant advances in genetic technology have greatly facilitated our ability to discover novel biological systems. Although this progression continues at a rapid pace, gaining a complete understanding of newly identified systems is sometimes hampered by a lack of appropriate pharmacological tools. Thus, our focus in this R01 application is to develop the pharmacological tools necessary to fully investigate the in vivo functions of the recently discovered neuropeptide S receptor. Neuropeptide S (NPS) is a 20 amino acid peptide that has been linked via its cognate G-protein coupled receptor to a variety of disease states including anxiety, narcolepsy, asthma, obesity, and potentially PTSD. Currently, there is a significant unmet need for non-peptide NPS molecular probes, particularly agonists. Filling this void with potent and selective ligands will expedite discovery of potential therapies that act on the NPS receptor system. Moreover, unlike peptides, small organic molecules are more likely to be systemically bioavailable and penetrate the blood brain barrier. The specific objectives of this application are based on preliminary data obtained during the first year of an R21 proposal to "Identify Small Molecules for the Neuropeptide S Receptor". While significant progress has been made toward identifying a core scaffold and delineating a rough NPS antagonist pharmacophore, much development work yet remains. First, there are no known small molecule agonist probes of NPS receptor function. This is significant because a growing body of evidence obtained from i.c.v. injections of the endogenous peptide supports the notion that agonist structures may prove to have a greater number of relevant disease targets than antagonists. Second, the most promising antagonist leads from a drug-like perspective are of moderate potency for at least one of the NPS isoforms (primarily 107N). The current application proposes to continue the synthesis and testing of novel NPS analogs based on our early leads. This approach will provide more drug-like small molecule probes of NPS receptor function and may ultimately lead to pharmacotherapies capable of treating anxiety, narcolepsy, asthma, obesity, or PTSD.