Natural Products as Potential Human Ether-A-Go-Go-Related Gene Channel Inhibitors – Screening of Plant-Derived Alkaloids

Abstract

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.

Isoquinoline alkaloids as prolyl oligopeptidase inhibitors

“…1) isolated from Macleaya cordata [25], two protoberberines corypalmine (IC 50 value 128.0 ± 10.5 μM; Fig. 1) and canadine (IC 50 value 152.0 ± 12.5 μM) from Corydalis cava [26], and finally by the aporphine type alkaloid N-methyllaurotetanine (IC 50 value 135.0 ± 11.7 μM) from Eschscholtzia californica [17].…”

“…[26]. Dihydrosanguinarine was isolated from a commercial extract of Macleaya cordata [25]. (-)-Platycerine was isolated from aerial parts of Argemone platyceras.…”

Effects of Chelidonium majus extracts and major alkaloids on hERG potassium channels and on dog cardiac action potential — A safety approach

“…Our results highlight the safety concerns regarding the internal use of C. majus: orally applied greater celandine products need cautious evaluation from the view of both hepatic and cardiovascular side effects. With regard to similar hERG blocking activity of related natural alkaloids [11], further studies are warranted to evaluate potential hERG-related safety aspects of medicinal plant extracts and to assess the clinical relevance of these findings.…”

“…However, several studies have demonstrated that berberine [6][7][8][9], chelerythrine [10], chelidonine [11], sanguinarine [11], and protopine [11] have hERG ion channel activities. The human ether-à-go-go-related gene (hERG, KCNH2, Kv11.1) encodes a cardiac voltage-gated potassium channel that provides the major repolarizing current (rapidly activating delayed rectifier potassium current, I Kr ) in phase 3 of the cardiac action potential.…”

“…Chelerythrine was also described to inhibit hERG current [10] and prolong action potential [12]. Although protopine also inhibits the hERG potassium current [11], in contrast with chelerythrine and berberine it shortens the action potential duration. This phenomenon is due to the multichannel effect of protopine, since protopine is not a selective ion channel antagonist.…”