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.
