Small Molecule Probes of the Neuropeptide S Receptor

描述（申请人提供）：基因技术的重大进展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步伐，获得一个新的系统的完整的理解，有时会受到缺乏适当的药理学工具。因此，我们在R 01申请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（Neuropeptide S，NPH）是一种由20个氨基酸组成的肽，通过其同源G蛋白偶联受体与多种疾病状态相连，包括焦虑、发作性睡病、哮喘、肥胖和潜在的PTSD。目前，对非肽类药物分子探针，特别是激动剂存在显著的未满足的需求。用有效的和选择性的配体填补这一空白将加速发现作用于β受体系统的潜在疗法。此外，与肽不同，有机小分子更有可能全身生物利用并穿透血脑屏障。本申请的具体目标是基于R21提案“识别神经肽S受体的小分子”第一年期间获得的初步数据。虽然已经取得了重大进展，确定一个核心支架和描绘一个粗略的拮抗剂药效团，许多开发工作仍然存在。首先，没有已知的小分子激动剂探针的β受体功能。这是重要的，因为从内源性肽的i. c. v.注射获得的越来越多的证据支持激动剂结构可能被证明比拮抗剂具有更多数量的相关疾病靶点的概念。第二，从药物样的角度来看，最有希望的拮抗剂先导物对至少一种α亚型（主要是107 N）具有中等效力。本申请提出基于我们的早期先导物继续合成和测试新的β-内酰胺类似物。这种方法将提供更多的药物样小分子探针的受体功能，并可能最终导致能够治疗焦虑症，嗜睡症，哮喘，肥胖症，或创伤后应激障碍的药物治疗。

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.