Deconvolution of Galbulimima bark pharmacology through chemical synthesis and target assignment

通过化学合成和目标分配对 Galbulimima 树皮药理学进行解卷积

• 批准号: 10682293
• 负责人: Laura M. Bohn
• 金额: $ 27.69万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-08 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10682293
• 关键词: Absence of pain sensation; Affect; Affinity; Agonist; Alkaloids; Analgesic and Antipyretic; Area; Behavior; Binding; Biological; Biological Assay; Bradycardia; Brain; Cell Respiration; Cells; Central Nervous System; Chemicals; Chemistry; Communities; Complex; Coupled; Coupling; Data; Development; Drug Kinetics; Family; Fever; G-Protein-Coupled Receptors; Goals; Grant; Grooming; Hallucinations; Hallucinogens; Human; In Vitro; Individual; Ingestion; Intestines; Investigation; Lead; Letters; Libraries; Ligands; Metabolism; Methods; Mus; Natural Products; Natural Remedy; Needles; Opioid; Opioid Receptor Binding; Oryctolagus cuniculus; Outcome; Papua New Guinea; Penetration; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Reaction; Reporting; Research; Research Personnel; Residual state; Resolution; Ritual compulsion; Role; Route; Sampling; Scientist; Second Messenger Systems; Spasm; Spasmolytics; Stimulant; Structure; Structure-Activity Relationship; Traditional Medicine; Translations; Trees; Variant; Work; addiction; analog; antagonist; chemical synthesis; combinatorial; decalin; follow-up; in vivo; interest; kappa opioid receptors; member; mu opioid receptors; novel therapeutics; pharmacologic; piperidine; plant metabolites; programs; receptor; scaffold; social stigma; structural biology; therapeutic development; treatment-resistant depression

Abstract The Galbulimima (GB) alkaloids are derived from the bark of the Galbulimima genus, which features in the traditional medicine and ritual of Papua New Guinea. GB alkaloid content varies markedly among individual trees, and only some bark samples cause hallucination. The number of alkaloids contained in the bark and their general scarcity complicate identification of the biomolecular targets and rigorous pharmacological characterization. Here we describe new chemical platforms for procurement of each Galbulimima alkaloid, the first new biological targets identified in over three decades and preliminary interrogation by pharmacology and structural biology. Viability of the synthetic platform is supported by route that reduce synthetic burden approximately three-fold. The first section of the grant demonstrates gram-scale Class Ia/b GB alkaloid accession by ligand-controlled cross-electrophile coupling (XEC). This strategy allows modular assembly of the carbocyclic (decalin) core with a variety of piperidine side-chains—motifs that define GB alkaloids. Whereas Class Ia targets mAChRs, scaffold rearrangement to Class Ib changes GPCR selectivity to ORs. Preliminary data suggests oxidized analogs shift OR antagonism toward agonism; in vivo data demonstrates rapid penetration of the brain to affect mouse behavior. Full interrogation of pharmacology and structural characterization of ligand-receptor complexes have begun to identify unique aspects of the "GB opioids." The second section explores gram-scale syntheses of Class II–IV via conversion of high fraction aromatic (FAr) scaffolds to high fraction sp3 (Fsp3), stereochemically-rich natural products. New cross-coupling reactions assemble aromatic feedstocks efficiently; we propose asymmetric variants to render existing racemic routes enantioselective. Importantly, existing and proposed routes are highly divergent and allow exploration of how structural variation correlates to selectivity among a human receptors. We identify another high affinity receptor associated with antispasmodic alkaloids and propose the syntheses of high-priority bradycardia agents. The synthetic platform outlined here combined with advances in robust cell-based second messenger assays now widely available for the receptor families of interest allow unprecedented ability to probe structure, function and selectivity of the GB alkaloids. Ultimately, we expect to identify enough ligand-receptor pairs to begin building a GB alkaloid-receptor interactome to predict structure-function relationships, supported by high-resolution experimental structures. This research holds great potential to identify privileged new scaffold leads for therapeutic development from plant metabolites already validated in humans.

抽象的 Galbulimima (GB) 生物碱源自 Galbulimima 属的树皮， 其中巴布亚新几内亚传统医学和仪式中的GB生物碱含量具有特色。 不同树木之间的差异显着，只有一些树皮样本会引起幻觉。 树皮中所含生物碱的数量及其普遍稀缺使生物碱的鉴定变得复杂 在这里，我们描述了新的生物分子靶点和严格的药理学特征。 用于采购每种 Galbulimima 生物碱的化学平台，第一个新的生物靶标 经过三十多年的鉴定和药理学和结构的初步审讯 合成平台的可行性得到了减少合成负担的途径的支持。 大约三倍。 拨款的第一部分展示了克级 Ia/b 级 GB 生物碱加入 通过配体控制的交叉亲电子偶联（XEC），该策略允许模块化组装。 具有多种哌啶侧链的碳环（十氢萘）核心——定义 GB 的基序 Ia 类靶标 mAChR 中的生物碱，Ib 类的支架重排会改变 GPCR 初步数据表明氧化类似物将 OR 拮抗作用转向。 激动；体内数据表明快速渗透大脑以影响小鼠行为。 配体-受体复合物的药理学和结构表征的研究 开始确定“GB 阿片类药物”的独特方面。 第二部分探讨了通过高位点转化来克级合成 II-IV 类化合物。 芳香族 (FAr) 支架到高含量 sp3 (Fsp3)、立体化学丰富的天然产物。 我们提出了新的交叉偶联反应有效地组装芳香族原料； 重要的是，现有的和拟议的种族路线具有对映选择性。 路线高度不同，可以探索结构变化如何与 我们确定了与人类受体之间的选择性相关的另一种高亲和力受体。 解痉生物碱并提出合成高优先级心动过缓剂。 这里概述的合成平台与强大的基于细胞的第二个技术的进步相结合 信使检测现已广泛用于感兴趣的受体家族，这使得前所未有的 最终，我们期望能够探测 GB 生物碱的结构、功能和选择性。 确定足够的配体-受体对，开始构建 GB 生物碱-受体相互作用组 在高分辨率实验结构的支持下预测结构-功能关系。 这项研究具有巨大的潜力，可以确定用于治疗的特殊新支架线索 由已经在人体中得到验证的植物代谢物开发而来。