Synthesis and Evaluation of Alkaloids to Probe Membrane Receptors

用于探针膜受体的生物碱的合成和评价

• 批准号: 10668500
• 负责人: Andrew Riley
• 金额: $ 37.82万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10668500
• 关键词: Agonist; Alkaloids; Area; Award; Biological Assay; Biological Process; Chemicals; Complex; Coupling; Development; Economics; Evaluation; Family; Future; G-Protein Signaling Pathway; G-Protein-Coupled Receptors; Health; Human; Indole Alkaloids; Ion Channel Gating; Laboratories; Libraries; Ligands; Medicine; Membrane; Methods; Monitor; Natural Products; Natural Source; Nicotinic Receptors; Opioid; Pharmacology; Protocols documentation; Research; Route; Signal Transduction; Synthesis Chemistry; Techniques; Therapeutic; Work; drug discovery; improved; inhibitor; insight; kappa opioid receptors; member; novel; rational design; receptor; scaffold; small molecule; tool

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.

摘要 新的小分子的发现，扰乱膜受体的功能，如G蛋白偶联 受体（GPCR）和配体门控离子通道（LGIC），仍然是至关重要的研究， 改善人类健康。天然产品特别适合这项任务，因为它们的结构 复杂性和独特的作用机制使它们成为上级化学探针和极好的起点 用于药物发现。Riley实验室专注于开发逐步经济的合成路线和强大的隔离 来获取这些复杂的天然产物支架。通过模块化全合成，半合成 方法和当代受体检测，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。本申请概述了我们的工作和未来的发展方向， 应用这些策略来研究烟碱乙酰胆碱受体（nAChRs）和κ阿片样物质 受体（κOR）分别作为LGIC和GPCR的代表。第一个研究领域建立在我们的工作基础上 最近确定了拟南芥生物碱家族的成员作为nAChRs的有效抑制剂，这是一个主要的 LGIC类，具有不寻常但理想的亚型选择性。在此期间，我们将开发精简的 合成化学，以获得整个类的苦碟子生物碱，并产生其 衍生物.通过将这些合成化学努力与扩大的筛选抗 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，我们将探索一个新的类， κOR激动剂是我们实验室最近发现的吲哚生物碱akuammicine的衍生物。我们 最初的研究确定这些阿库阿米辛衍生物是有效的偏向性激动剂，其优先激活 G蛋白信号通路利用隔离协议，提供综合有用的 复杂的生物碱直接从他们的天然来源，我们将采用后期多样化技术， 快速产生新的衍生物，探测κOR内的配体-受体相互作用，并监测它们的能力， 启动阿片类信号级联反应我们希望这项研究的结果将超越nAChR， κOR，并可应用于其他治疗相关的LGIC和GPCR，从而产生显著影响 通过揭示合理设计这些重要膜的配体的新方向， 受体。