Sesquiterpene Lactone Derivatives of Ambrosia artemisiifolia Act as Agonists of the Transient Receptor Potential Ankyrin 1 Ion Channel.

Background: Transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are key nociceptive ion channels involved in chemosensation, pain signaling, and neurogenic inflammation. Several sesquiterpene lactones target TRPA1, but the activity profile of these secondary metabolites of the common ragweed (Ambrosia artemisiifolia) remains uncharacterized. Purpose: The purpose of this study was to explore the activity of five ragweed sesquiterpene lactones on TRPA1 and TRPV1, respectively. Methods: We investigated the effects of five ragweed-derived sesquiterpene lactones-acetoxydihydrodamsin, costunolide, isoalantolactone, peruvin, and psilostachyin-on TRPA1 and TRPV1 using 45Ca2+ uptake in receptor-overexpressing CHO cells and covalent docking to human TRPA1. Results: Costunolide, isoalantolactone and acetoxydihydrodamsin induced TRPA1 activation (counts per minute of 45Ca2+ uptake at 40 µM concentration: 5070 ± 346.5, 10,197 ± 1237, 3704 ± 1634, respectively) but not TRPV1 activation, as demonstrated by Ca2+ influx. Acetoxydihydrodamsin induced concentration-dependent TRPA1 activation that was significantly inhibited by 10 µM of the selective antagonist HC-030031. Docking studies demonstrated covalent interactions of costunolide, isoalantolactone, and acetoxydihydrodamsin (-47.3, -51.5, and -45.0 kcal/mol FITTED score) with the electrophile-sensitive binding region of TRPA1. Conclusions: Ragweed sesquiterpene lactones act as TRPA1 agonists without detectable TRPV1 activation. This study provides the first data identifying acetoxydihydrodamsin as a TRPA1 agonist, expanding the pharmacological map of ragweed sesquiterpene lactones. These results suggest that these metabolites may contribute to both the irritant properties and the pharmacological potentials of A. artemisiifolia.