Discovery of analgesic diterpenoid alkaloids from medicinal Aconitum plants using a metabolomic approach

使用代谢组学方法从药用乌头植物中发现镇痛二萜生物碱

基本信息

批准号：
10629875
负责人：
EDWARD JAMES KENNELLY
金额：
$ 14.6万
依托单位：
HERBERT H. LEHMAN COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-01 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10629875
关键词：
Aconitum Alkaloids American Analgesics Animals Anti-Inflammatory Agents Asia Asian Biological Biological Assay Biological Testing Cannabidiol Capsaicin Cardiotoxicity Chemical Structure Chemicals Chemistry Chinese Chinese Traditional Medicine Complex Data Discriminant Analysis Diterpenes Europe Family Future Goals Lead Liquid Chromatography Manuscripts Medicine Modeling Modernization Molecular Molecular Target Natural Products Natural Products Chemistry North America Opioid Receptor Opium Outcomes Research Pain Pain management Pattern Pharmaceutical Preparations Pharmacopoeias Physicians Phytochemical Plant Extracts Plants Property Public Health Ranunculaceae Reporting Research Safety Salicylic Acids Source Structure System Techniques Technology Testing Therapeutic Therapeutic Uses Traditional Medicine Training Underrepresented Populations United States National Institutes of Health Variant Zebrafish cannabinoid receptor career development drug discovery endogenous cannabinoid system graduate student in vivo metabolomics non-opioid analgesic novel novel therapeutics opioid epidemic opioid withdrawal preclinical study response scaffold symposium tandem mass spectrometry time of flight mass spectrometry tool undergraduate student

项目摘要

Project Summary The opioid crisis has made it apparent that there is a tremendous need for analgesic drugs that do not target the opioid receptors. Plants are an ideal source for developing these drugs, as they produce a diverse range of natural products with analgesic activity, like salicylic acid, capsaicin, and cannabidiol. These compounds act on different pain response systems in animals, like the endocannabinoid system. Aconitum, a genus of plants in the Ranunculaceae family, is used in different traditional medicine systems around the world, often for its analgesic and/or anti-inflammatory properties. In traditional Chinese medicine, Aconitum carmichaelii has been used for thousands of years, and the bioactivity has been associated mainly with its diterpenoid alkaloid content. While these compounds have been shown to be potent analgesics, some are cardiotoxic as well. Despite their similar medicinal use, American Aconitum species have not been as thoroughly studied in terms of chemistry or bioactivity. The long-term goal of our research is to identify, characterize, and quantify therapeutic components in plants used in traditional medicine systems as sources of new drugs. The overall objective of this project is to analyze Aconitum in North America, specifically regarding its analgesic diterpenoid alkaloids that lack cardiotoxicity as compared to the better-studied Asian species. Our initial studies on Aconitum showed significant variation in chemical structures and amounts of selected diterpenoid alkaloids, and we have identified fuziline and neoline from Asian Aconitum carmichaelii as having analgesic activity without being cardiotoxic. Other studies have found that these diterpenoid alkaloids target the cannabinoid receptors. Thus, we hypothesize that a small group of diterpenoid alkaloids in American Aconitum species will have analgesic properties without the concomitant cardiotoxicity. We will test this hypothesis by carrying out three aims. In Aim 1, we will collect and examine eight Aconitum species and determine patterns of diterpenoid alkaloids using untargeted LC-QToF-MS metabolomic studies. In Aim 2, we will assess plant extracts, fractions, and purified diterpenoid alkaloids from American Aconitum species in high-throughput zebrafish assays to identify bioactive compounds that target pain but do not have cardiotoxicity. In Aim 3, we will use a targeted LC-TQD-MS analysis to quantify the target analgesic compounds in the eight Aconitum species, and join the metabolomic and biological data obtained in Aims 1 and 2 together through novel metabolomic platforms, such as NP analyst, to create a molecular network of analgesic compounds produced by Aconitum that lack cardiotoxicity Together, the completion of these three aims will result in a group of analgesic compounds that will be prioritized for further preclinical studies. This project will also train undergraduate and graduate students from underrepresented groups in modern applications and technologies of natural product chemistry and provide them with opportunities for career development by presenting at conferences and authoring manuscripts.

项目概要阿片类药物危机清楚地表明，对非靶向镇痛药物的巨大需求阿片受体。植物是开发这些药物的理想来源，因为它们产生多种具有镇痛活性的天然产物，如水杨酸、辣椒素和大麻二酚。这些化合物作用于动物中不同的疼痛反应系统，例如内源性大麻素系统。乌头属（Aconitum），植物属毛茛科，在世界各地的不同传统医学体系中使用，通常因其镇痛作用和/或抗炎特性。在传统中医中，Aconitum carmichaelii 已被用于几千年来，其生物活性主要与其二萜生物碱含量有关。尽管这些化合物已被证明是有效的镇痛药，有些还具有心脏毒性。尽管他们相似药用方面，美洲乌头物种在化学或化学方面尚未得到彻底的研究。生物活性。我们研究的长期目标是识别、表征和量化治疗成分在传统医学系统中用作新药来源的植物中。该项目的总体目标是分析北美的乌头，特别是其缺乏的镇痛二萜生物碱与经过深入研究的亚洲物种相比，其心脏毒性更大。我们对乌头的初步研究表明，选定的二萜生物碱的化学结构和含量的变化，我们已经鉴定出夫子林来自亚洲乌头的新林具有镇痛活性，但没有心脏毒性。其他研究发现这些二萜生物碱靶向大麻素受体。因此，我们假设美洲乌头属物种中的一小部分二萜生物碱将具有镇痛特性，而无需伴随的心脏毒性。我们将通过实现三个目标来检验这一假设。在目标 1 中，我们将收集并使用非靶向 LC-QToF-MS 检查八种乌头属物种并确定二萜生物碱的模式代谢组学研究。在目标 2 中，我们将评估植物提取物、级分和纯化的二萜生物碱美洲乌头属物种在高通量斑马鱼检测中鉴定针对疼痛的生物活性化合物但不具有心脏毒性。在目标 3 中，我们将使用有针对性的 LC-TQD-MS 分析来量化目标八种乌头属植物中的镇痛化合物，并结合在中获得的代谢组学和生物学数据通过新颖的代谢组学平台（例如 NP 分析师）将目标 1 和 2 结合在一起，创建分子网络乌头产生的缺乏心脏毒性的镇痛化合物共同完成这三个任务目标将产生一组镇痛化合物，这些化合物将优先用于进一步的临床前研究。这该项目还将为来自代表性不足群体的本科生和研究生提供现代培训天然产物化学的应用和技术，并为他们提供职业机会通过在会议上发言和撰写手稿来发展。