Inhibition of the hERG channel delays repolarization and prolongs the QT interval and cardiac action potential which can lead to sudden death. Several drugs have been withdrawn from the market due to hERG channel inhibition. In the search of hERG channel inhibitors of natural origin, we established an HPLC-based profiling approach which combines HPLC-microfractionation and bioactivity testing on Xenopus laevis oocytes. The methanolic extract of the TCM herbal drug Coptidis rhizoma (Coptis chinensis Franch., Ranunculaceae) reduced the peak tail hERG current by 31.7 ± 2.0% at 100 µg/mL. HPLC-based activity profiling pointed towards berberine as the active constituent. However, hERG inhibition by 100 µM of a reference sample of berberine (16.3 ± 1.6%) was less pronounced than previously reported. Subsequent LC-PDA-MS analysis showed that berberine collected by microfractionation of the Coptis extract had been, in part, transformed to active dihydroberberine. Formic acid added to the HPLC mobile phase to reduce peak tailing of protoberberine alkaloids acted as a reducing reagent according to the mechanism of the Leuckart-Wallach reaction. Among other structurally related protoberberines tested, dihydroberberine (30.1 ± 10.1% at 100 µM) was the most potent hERG inhibitor.

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Inhibition of the cardiac human ether-a-go-go-related gene channel is a problematic off-target pharmacological activity and, hence, a major safety liability in clinical practice. Several non-cardiac drugs have been restricted in their use, or even removed from the market due to this potentially fatal adverse effect. Comparatively little is known about the human ether-a-go-go-related gene inhibitory potential of plant-derived compounds. In the course of an ongoing human ether-a-go-go-related gene in vitro study, a total of 32 structurally diverse alkaloids of plant origin as well as two semi-synthetically obtained protoberberine derivatives were screened by means of an automated Xenopus oocyte assay. Protopine, (+)-bulbocapnine, (+)-N-methyllaurotetanine, (+)-boldine, (+)-chelidonine, (+)-corynoline, reserpine, and yohimbine reduced the human ether-a-go-go-related gene current by ≥ 50% at 100 µM, and were submitted to concentration-response experiments. Our data show that some widely occurring plant-derived alkaloids carry a potential risk for human ether-a-go-go-related gene toxicity.

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Inhibition of the human ether-a-go-go-related gene channel is the single most important risk factor leading to acquired long QT syndrome. Drug-induced QT prolongation can cause severe cardiac complications, including arrhythmia, and is thus a liability in drug development. Considering the importance of the human ether-a-go-go-related gene channel as an antitarget and the daily intake of plant-derived foods and herbal products, surprisingly few natural products have been tested for channel blocking properties. In an assessment of possible human ether-a-go-go-related gene liabilities, a selection of widely used herbal medicines and edible plants (vegetables, fruits, and spices) was screened by means of a functional two-microelectrode voltage-clamp assay with Xenopus oocytes. The human ether-a-go-go-related gene channel blocking activity of selected extracts was investigated with the aid of a high-performance liquid chromatography-based profiling approach, and attributed to tannins and alkaloids. Major European medicinal plants and frequently consumed food plants were found to have a low risk for human ether-a-go-go-related gene toxicity.