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

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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.