Small Molecules for the Neuropeptide S Receptor System

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。尽管这一进展仍在快速进行，但有时由于缺乏适当的药理学工具，对新发现的系统的全面了解会受到阻碍。因此，我们在R21应用中的重点是为最近发现的神经肽S受体开发药理工具。 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、肥胖和精神分裂症。目前，对非肽NPS分子探针，特别是拮抗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。 我们的实验室投资了一个项目，为NPS受体系统识别非肽小分子。我们已经开发了一种基于平板的快速功能分析，并开始了旨在发现非肽小分子的药物化学计划。自从我们的项目启动以来，我们已经确定了一个激动剂铅支架和一个拮抗剂铅支架。有鉴于此，R21应用的目标是进一步探索NPS配体的构效关系，并为NPS受体系统开发高亲和力的激动剂和拮抗剂。 我们的策略利用计算机建模来整合来自我们内部筛选工作的结构信息和基于同源性的药效团鉴定(后叶加压素/催产素)。我们建议使用这些知识在加权多样性方法中合成新的化合物，而不是一般的多样性筛选。这种方法将提供NPS受体功能的小分子探针，并最终可能导致能够治疗焦虑、发作性睡病、哮喘、肥胖或精神分裂症的类药物实体。

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 R21 application is to develop pharmacological tools for 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 schizophrenia. Currently, there is a significant unmet need for non-peptide NPS molecular probes, particularly antagonists. 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. Our laboratory has invested in a program to identify non-peptide small molecules for the NPS receptor system. We have developed a rapid, plate-based functional assay and begun a medicinal chemistry program aimed at discovering non-peptide small molecules. Since initiating our program, we have identified an agonist lead scaffold and an antagonist lead scaffold. With this in mind, the goals of this R21 application are to further explore the structure-activity relationships of NPS ligands and to develop high affinity agonists and antagonists for the NPS receptor system. Our strategy utilizes computer modeling to integrate structural information from our in-house screening effort and homology based pharmacophore identification (vasopressin/oxytocin). We propose to synthesize new compounds using this knowledge in a weighted diversity approach rather than a general diversity screen. This approach will provide small molecule probes of NPS receptor function and may ultimately lead to drug-like entities capable of treating anxiety, narcolepsy, asthma, obesity, or schizophrenia.