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， 这是传统医学和巴布亚新几内亚仪式的特色。 GB生物碱含量 在各个树木中，只有一些树皮样品会引起幻觉。 树皮中包含的生物碱数量及其一般稀缺性使人们对 生物分子靶标和严格的药物表征。在这里我们描述新的 每个Galbulimima生物碱采购的化学平台，这是第一个新的生物学靶标 在三十多年来确定，并通过药理学和结构进行初步询问 生物学。合成平台的可行性由减少合成燃烧的路线支持 大约三倍。 赠款的第一部分展示了革兰氏规模的IA/B类GB生物碱加入 由配体控制的跨电动耦合（XEC）。该策略允许模块化组装 带有各种哌啶侧链的碳环（脱甲酸）核心 - 定义GB的含量 生物碱。 IA级目标是MACHR，而脚手架重排以Class IB更改GPCR 对ORS的选择性。初步数据表明氧化的类似物转移或对抗向 激动体内数据表明大脑快速渗透以影响小鼠行为。满的 对配体复合物复合物的药理学和结构表征的询问具有 开始确定“ GB阿片类药物”的独特方面。 第二部分通过高转换来探索II – IV类的革兰氏尺度合成 分数芳香族（FAR）支架至高分子SP3（FSP3），立体化学上丰富的天然产物。 新的交叉偶联反应有效地组装了芳香原料；我们提出不对称 变体以使现有的外星人路线对映选择性。重要的是，现有和建议 路线高度分歧，允许探索结构变化与 人类受体之间的选择性。我们确定与 脉冲生物碱和提案的高优先性心动过缓剂的合成。 此处概述的合成平台与强大的基于细胞的第二相结合 现在广泛用于感兴趣的受体家族的Messenger Assas允许前所未有 能够探测GB生物碱的结构，功能和选择性。最终，我们期望 识别足够的配体 - 受体对开始构建GB生物碱 - 受体相互作用组 预测由高分辨率实验结构支持的结构功能关系。 这项研究具有识别特权新支架的巨大潜力的巨大潜力 从人类中已经证实的植物代谢产物的发展。