Stereoselective inhibition of the hERG1 potassium channel
A growing number of drugs have been shown to prolong cardiac repolarization, predisposing individuals to life-threatening ventricular arrhythmias known as Torsades de Pointes. Most of these drugs are known to interfere with the human ether à-gogo related gene 1 (hERG1) channel, whose curren...
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doaj-eea6bcfafd964aa79a3ea5c8c44537552020-11-24T23:02:29ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122010-11-01110.3389/fphar.2010.001377878Stereoselective inhibition of the hERG1 potassium channelLiliana eSintra Grilo0Liliana eSintra Grilo1Pierre-Alain eCarrupt2Hugues eAbriel3University of BernUniversity of GenevaUniversity of GenevaUniversity of BernA growing number of drugs have been shown to prolong cardiac repolarization, predisposing individuals to life-threatening ventricular arrhythmias known as Torsades de Pointes. Most of these drugs are known to interfere with the human ether à-gogo related gene 1 (hERG1) channel, whose current is one of the main determinants of action potential duration. Prolonged repolarization is reflected by lengthening of the QT interval of the electrocardiogram, as seen in the suitably named drug-induced long QT syndrome. Chirality (presence of an asymmetric atom) is a common feature of marketed drugs, which can therefore exist in at least two enantiomers with distinct three-dimensional structures and possibly distinct biological fates. Both the pharmacokinetic and pharmacodynamic properties can differ between enantiomers, as well as also between individuals who take the drug due to metabolic polymorphisms. Despite the large number of reports about drugs reducing the hERG1 current, potential stereoselective contributions have only been scarcely investigated. In this review, we present a non-exhaustive list of clinically important molecules which display chiral toxicity that may be related to hERG1-blocking properties. We particularly focus on methadone cardiotoxicity, which illustrates the importance of the stereoselective effect of drug chirality as well as individual variations resulting from pharmacogenetics. Furthermore, it seems likely that, during drug development, consideration of chirality in lead optimization and systematic assessment of the hERG1 current block with all enantiomers could contribute to the reduction of the risk of drug-induced LQTS.http://journal.frontiersin.org/Journal/10.3389/fphar.2010.00137/fullLong QT Syndromeenantiomercardiotoxicitycardiac channelopathieshERG1voltage-gated potassium channel |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Liliana eSintra Grilo Liliana eSintra Grilo Pierre-Alain eCarrupt Hugues eAbriel |
spellingShingle |
Liliana eSintra Grilo Liliana eSintra Grilo Pierre-Alain eCarrupt Hugues eAbriel Stereoselective inhibition of the hERG1 potassium channel Frontiers in Pharmacology Long QT Syndrome enantiomer cardiotoxicity cardiac channelopathies hERG1 voltage-gated potassium channel |
author_facet |
Liliana eSintra Grilo Liliana eSintra Grilo Pierre-Alain eCarrupt Hugues eAbriel |
author_sort |
Liliana eSintra Grilo |
title |
Stereoselective inhibition of the hERG1 potassium channel |
title_short |
Stereoselective inhibition of the hERG1 potassium channel |
title_full |
Stereoselective inhibition of the hERG1 potassium channel |
title_fullStr |
Stereoselective inhibition of the hERG1 potassium channel |
title_full_unstemmed |
Stereoselective inhibition of the hERG1 potassium channel |
title_sort |
stereoselective inhibition of the herg1 potassium channel |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Pharmacology |
issn |
1663-9812 |
publishDate |
2010-11-01 |
description |
A growing number of drugs have been shown to prolong cardiac repolarization, predisposing individuals to life-threatening ventricular arrhythmias known as Torsades de Pointes. Most of these drugs are known to interfere with the human ether à-gogo related gene 1 (hERG1) channel, whose current is one of the main determinants of action potential duration. Prolonged repolarization is reflected by lengthening of the QT interval of the electrocardiogram, as seen in the suitably named drug-induced long QT syndrome. Chirality (presence of an asymmetric atom) is a common feature of marketed drugs, which can therefore exist in at least two enantiomers with distinct three-dimensional structures and possibly distinct biological fates. Both the pharmacokinetic and pharmacodynamic properties can differ between enantiomers, as well as also between individuals who take the drug due to metabolic polymorphisms. Despite the large number of reports about drugs reducing the hERG1 current, potential stereoselective contributions have only been scarcely investigated. In this review, we present a non-exhaustive list of clinically important molecules which display chiral toxicity that may be related to hERG1-blocking properties. We particularly focus on methadone cardiotoxicity, which illustrates the importance of the stereoselective effect of drug chirality as well as individual variations resulting from pharmacogenetics. Furthermore, it seems likely that, during drug development, consideration of chirality in lead optimization and systematic assessment of the hERG1 current block with all enantiomers could contribute to the reduction of the risk of drug-induced LQTS. |
topic |
Long QT Syndrome enantiomer cardiotoxicity cardiac channelopathies hERG1 voltage-gated potassium channel |
url |
http://journal.frontiersin.org/Journal/10.3389/fphar.2010.00137/full |
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