Stereoselective Blockage of Quinidine and Quinine in the hERG Channel and the Effect of Their Rescue Potency on Drug-Induced hERG Trafficking Defect

Abstract

Diastereoisomers of quinidine and quinine are used to treat arrhythmia and malaria, respectively. It has been reported that both drugs block the hERG (human ether-a-go-go-related gene) potassium channel which is essential for myocardium repolarization. Abnormality of repolarization increases risk of arrhythmia. The aim of our research is to study and compare the impacts of quinidine and quinine on hERG. Results show that both drugs block the hERG channel, with quinine 14-fold less potent than quinidine. In addition, they presented distinct impacts on channel dynamics. The results imply their stereospecific block effect on the hERG channel. However, F656C-hERG reversed this stereoselectivity. The mutation decreases affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. These data suggest that F656 residue contributes to the stereoselective pocket for quinidine and quinine. Further study demonstrates that both drugs do not change hERG protein levels. In rescue experiments, we found that they exert no reverse effect on pentamidine- or desipramine-induced hERG trafficking defect, although quinidine has been reported to rescue trafficking-deficient pore mutation hERG G601S based on the interaction with F656. Our research demonstrated stereoselective effects of quinidine and quinine on the hERG channel, and this is the first study to explore their reversal potency on drug-induced hERG deficiency.

Oral quinine sulfate for the treatment of electrical storm and prevention of recurrent shocks in Brugada syndrome after failed cilostazol therapy

“…The absence of QT prolongation and lower incidence of torsades with quinine is due to its stereoselective effect, resulting in 14 times less potency in blocking the hERG channel, the potassium channel essential for myocardial repolarization. 13 Unlike quinidine, quinine has the advantage of being readily available in most countries, and hence, further studies are needed to assess the effectiveness of oral quinine sulfate in the treatment of ventricular arrhythmias in BrS patients. Quinine remains the most commonly used antimalarial therapy despite toxicity concerns, especially in children.…”

Biologically active quinoline and quinazoline alkaloids part II

“…The results also indicate stereospecific block effect on the hERG channel, but F656C‐hERG reversed this stereoselectivity. The mutation decreased affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C‐hERG blockage . Quinine also stimulated adipogenesis through ERK/S6 signaling, acting at least partly via the bitter taste receptor T2R106 …”

“…The diastereoisomeric quinoline akaloids quinidine and quinine, which are used to treat arrhythmia and malaria, respectively, block the hERG (human ether‐a‐go‐go‐related gene) potassium channel, which is essential for myocardium repolarization . Quinine was 14‐fold less potent than quinidine.…”

“…The mutation decreased affinity of the two drugs with hERG, and quinine was more potent than quinidine in F656C-hERG blockage. 157 Quinine also stimulated adipogenesis through ERK/S6 signaling, acting at least partly via the bitter taste receptor T2R106. 158 A new quinoline alkaloid, 8-hydroxy-9-methyl-furo[2,3-b]quinolin-4(9H)-one (178) (Figure 22), together with isopteleine, robustine, -fagarine, isodictamnine, and skimmianine were isolated from D. angustifolius.…”

Modification of distinct ion channels differentially modulates Ca2+ dynamics in primary cultured rat ventricular cardiomyocytes

“…We demonstrate that four clinically-used drugs including cisapride, dofetilide, sotalol and quinidine that were withdrawn due to their ability to produce LQT also induce SCO bursts in ventricular cardiomyocyte cultures. It should be mentioned that cisapride, dofetilide, and sotalol directly inhibit hERG channel activity whereas quinidine decreases the surface expression of hERG channels by suppressing hERG channel translocation to cell membrane surface37. These data imply that regardless of mode of action, functional suppression of hERG channel activity by cardiotoxicants produces similar characteristic SCO prolongation/occurrence of SCO bursts.…”