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The traditional Japanese phytomedicine rikkunshito is traditionally used for the treatment of gastrointestinal motility disorders, cachexia and nausea. These effects indicate \(5-HT_{3}\) receptor antagonism, due to the involvement of these receptors in such pathophysiological processes. E.g., setrons, specific \(5-HT_{3}\) receptor antagonists are the strongest antiemetics, developed so far. Therefore, the antagonistic effects of the eight rikkunshito constituents at heterologously expressed \(5-HT_{3A}\)receptors were analyzed using the two-electrode voltage-clamp technique. The results indicate that tinctures from \(\textit {Aurantii, Ginseng, Zingiberis, Atractylodis}\) and \(\it Glycyrrhiza\) inhibited the \(5-HT_{3A}\) receptor response, whereas the tinctures of \(\textit {Poria cocos, Jujubae}\) and \(\it Pinellia\) exhibited no effect. Surprisingly, the strongest antagonism was found for \(\it Glycyrrhiza\), whereas the \(\it Zingiberis\) tincture, which is considered to be primarily responsible for the effect of rikkunshito, exhibited the weakest antagonism of \(5-HT_{3A}\) receptors. Rikkunshito contains various vanilloids, ginsenosides and flavonoids, a portion of which show an antagonistic effect on \(5-HT_{3}\) receptors. A screening of the established ingredients of the active rikkunshito constituents and related substances lead to the identification of new antagonists within the class of flavonoids. The flavonoids (-)-liquiritigenin, glabridin and licochalcone A from \(\it Glycyrrhiza\) species were found to be the most effective inhibitors of the 5-HT-induced currents in the screening. The flavonoids (-)-liquiritigenin and hesperetin from \(\it Aurantii\) inhibited the receptor response in a non-competitive manner, whereas glabridin and licochalcone A exhibited a potential competitive antagonism. Furthermore, licochalcone A acts as a partial antagonist of \(5-HT_{3A}\) receptors. Thus, this study reveals new \(5-HT_{3A}\) receptor antagonists with the aid of increasing the comprehension of the complex effects of rikkunshito. |
