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生物系统的能力。虽然这一进展继续以快速的速度进行，但对新发现的系统的完全了解有时会因为缺乏适当的药理学工具而受到阻碍。因此，我们在R01中的应用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是一种20个氨基酸的多肽，通过其同源的G蛋白偶联受体与多种疾病状态联系在一起，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仍未得到满足。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，有机小分子更有可能在系统内获得生物利用度，并穿透血脑屏障。本申请的具体目标是基于在R21提案的第一年中获得的初步数据，该提案的目的是“识别神经肽S受体的小分子”。虽然在确定核心支架和描绘粗略的NPS拮抗剂药效团方面已经取得了重大进展，但仍有许多开发工作要做。首先，目前还没有已知的NPS受体功能的小分子激动剂探针。这一点意义重大，因为从I.C.V.获得的证据越来越多。注射内源性多肽支持这样的观点，即激动剂结构可能比拮抗剂具有更多相关的疾病靶点。其次，从类药物的角度来看，最有希望的拮抗剂先导对至少一种NPS亚型(主要是107N)具有中等效力。目前的应用建议在我们早期领先的基础上继续合成和测试新型NPS类似物。这种方法将为NPS受体功能提供更多类似药物的小分子探针，并最终可能导致能够治疗焦虑、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.