Small Molecules for the Neuropeptide S Receptor System

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。虽然这一进展仍在快速进行，但对新发现的系统的全面了解有时会因缺乏适当的药理学工具而受到阻碍。因此，我们在R21应用中的重点是为最近发现的神经肽S受体开发药理学工具。 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，包括焦虑症、嗜睡症、哮喘、肥胖症和精神分裂症。目前，对非肽类药物分子探针，特别是拮抗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。 我们的实验室已经投资了一个项目，以确定非肽小分子的受体系统。我们已经开发了一种快速的，基于板的功能测定，并开始了一项旨在发现非肽小分子的药物化学计划。自从启动我们的计划，我们已经确定了激动剂铅支架和拮抗剂铅支架。考虑到这一点，该R21应用的目标是进一步探索β受体配体的结构-活性关系，并开发β受体系统的高亲和力激动剂和拮抗剂。 我们的策略是利用计算机建模来整合我们内部筛选工作和基于同源性的药效团鉴定（加压素/催产素）的结构信息。我们建议合成新的化合物，使用这种知识的加权多样性的方法，而不是一个一般的多样性屏幕。这种方法将提供小分子探针的受体功能，并可能最终导致药物样实体能够治疗焦虑症，嗜睡症，哮喘，肥胖症，或精神分裂症。

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.