title: 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.
authors: Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland.
authors: Anja
authors: A
authors: Schramm
authors: Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
authors: Priyanka
authors: P
authors: Saxena
authors: ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Charles University, Hradec Králové, Czech Republic.
authors: Jakub
authors: J
authors: Chlebek
authors: ADINACO Research Group, Department of Pharmaceutical Botany and Ecology, Charles University, Hradec Králové, Czech Republic.
authors: Lucie
authors: L
authors: Cahlíková
authors: Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
authors: Igor
authors: I
authors: Baburin
authors: Department of Pharmacology and Toxicology, University of Vienna, Vienna, Austria.
authors: Steffen
authors: S
authors: Hering
authors: Division of Pharmaceutical Biology, University of Basel, Basel, Switzerland.
authors: Matthias
authors: M
authors: Hamburger
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000470:Alkaloids / Q000494:pharmacology*; D000818:Animals; D001600:Berberine Alkaloids / Q000494:pharmacology*; D001688:Biological Products / Q000494:pharmacology*; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors*; D005260:Female; D006801:Humans; D020128:Inhibitory Concentration 50; D009865:Oocytes; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D014982:Xenopus laevis
chemical_list: D000470:Alkaloids; D001600:Berberine Alkaloids; D001688:Biological Products; D051638:Ether-A-Go-Go Potassium Channels; C496884:KCNH1 protein, human; D026902:Potassium Channel Blockers; C009090:protoberberine