Synthesis and Evaluation of Alkaloids to Probe Membrane Receptors

摘要 扰乱膜受体功能的新小分子的发现，如G蛋白偶联 受体(GPCRs)和配体门控离子通道(LGIC)对研究和 改善人类健康。天然产品特别适合于这项任务，因为它们的结构性 复杂性和独特的作用机制使它们成为优越的化学探针和良好的起点 用于药物研发。莱利实验室专注于开发步骤经济的合成路线和稳健的分离 访问这些复杂的天然产品支架的协议。通过模块化全合成，半合成 方法和当代受体分析，我们将天然产物转化为高效和选择性的工具 用于研究膜受体。此应用程序概述了我们在以下方面的工作和未来方向 应用这些策略研究烟碱型乙酰胆碱受体(NAChRs)和kappa阿片类物质 受体(κOR)分别作为IgIC和GPCR3的代表。第一个研究领域建立在我们工作的基础上 该组织最近发现马兜铃生物碱家族的成员是nAChRs的有效抑制剂，nAChRs是一种主要的 LGIC类，具有不同寻常但令人满意的亚型-选择性。在本次颁奖期间，我们将开发流线型 合成化学，以访问整个马兜铃生物碱类并生成其大型文库 衍生品。通过将这些合成化学努力与筛选抗病毒活性的扩展能力结合起来 一系列nAChR亚型和其他膜受体，这项工作将提供新的化学工具来探测 特定nAChR亚型的生物学功能。在第二个研究领域，我们将探索一类新的 κ或激动剂来源于我们实验室最近发现的吲哚生物碱阿库米星。我们的 初步研究证实，这些阿卡米星衍生物是有效的偏向激动剂，优先激活 G蛋白信号通路。利用隔离协议提供综合有用的数量 复杂的生物碱直接来自其自然来源，我们将采用后期状态多样化技术来 快速生成新的衍生物，探测κOR中的配体-受体相互作用并监测它们的能力 以启动阿片信号级联反应。我们预计这项研究的结果将超出nAChR和 κOR AND可应用于其他治疗相关的LGIC和GPCR，从而产生重大影响 通过揭示合理设计这些重要膜的配体的新方向 感受器。

ABSTRACT The discovery of new small molecules that perturb the function of membrane receptors, like G-protein coupled receptors (GPCRs) and ligand-gated ion channels (LGIC), remains critically important to the study and improvement of human health. Natural products are particularly well-suited for this task, as their structural complexity and unique mechanism of action make them superior chemical probes and excellent starting points for drug discovery. The Riley lab is focused on developing step-economic synthetic routes and robust isolation protocols to access these complex natural product scaffolds. Through modular total syntheses, semi-synthetic methods, and contemporary receptor assays, we transform natural products into highly potent and selective tools for studying membrane receptors. This application describes an overview of our work and future directions in applying these strategies to investigate the nicotinic acetylcholine receptors (nAChRs) and the kappa opioid receptor (κOR) as representative LGIC and GPCR, respectively. The first research area builds upon our work that recently identified members of the Aristotelia alkaloid family as potent inhibitors of the nAChRs, a major class of LGICs, with an unusual yet desirable subtype-selectivity. During this award, we will develop streamlined synthetic chemistry to access the entire class of Aristotelia alkaloids and generate large libraries of their derivatives. By coupling these synthetic chemistry efforts with an expanded ability to screen for activity against an array of nAChR subtypes and other membrane receptors, this work will deliver new chemical tools to probe the biological function of specific nAChR subtypes. In the second research area, we will explore a novel class of κOR agonists derived from the indole alkaloid akuammicine that were recently discovered in our laboratory. Our initial studies identified these akuammicine derivatives are potent biased agonist that preferentially activate the G-protein signaling pathway. Leveraging isolation protocols that provide synthetically useful quantities of complex alkaloids directly from their natural sources, we will employ late-state diversification techniques to rapidly generate novel derivatives that probe ligand-receptor interactions within the κOR and monitor their ability to initiate opioid signaling cascades. We expect the results from this research will reach beyond the nAChR and κOR and can be applied to other therapeutically relevant LGICs and GPCRs, thereby having a significant impact on drug discovery by revealing new directions to rationally design ligands for these important membrane receptors.