2 An Overview of Class III Electrophysiological Agents: A New Generation of Antiarrhythmic Therapy

Morgan, Thomas K.; Sullivan, M.

doi:10.1016/s0079-6468(08)70005-5

Cited by 49 publications

(35 citation statements)

References 131 publications

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“…The classical properties of hERG blockers, a basic nitrogen and an aromatic moiety, position at the positively ionizable feature and the three hydrophobes, respectively. This distribution of features of the hypothetical pharmacophore is similar to those reported by other investigators [17,38].…”

Section: In Silico Prediction Systems For Chemical Block Of Hergsupporting

confidence: 90%

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

et al. 2008

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A variety of compounds with different chemical properties directly interact with the cardiac repolarizing K + channel encoded by the human ether-a-go-go-related gene (hERG). This causes acquired forms of QT prolongation, which can result in lethal cardiac arrhythmias, including torsades de pointes one of the most serious adverse effects of various therapeutic agents. Prediction of this phenomenon will improve the safety of pharmacological therapy and also facilitate the process of drug development. Here we propose a strategy for the development of an in silico system to predict the potency of chemical compounds to block hERG. The system consists of two sequential processes. The first process is a ligand-based prediction to estimate half-maximal concentrations for the block of compounds inhibiting hERG current using the relationship between chemical features and activities of compounds. The second process is a protein-based prediction that comprises homology modeling of hERG, docking simulation of chemical-channel interaction, analysis of the shape of the channel pore cavity, and Brownian dynamics simulation to estimate hERG currents in the presence and absence of chemical blockers. Since each process is a combination of various calculations, the criterion for assessment at each calculation and the strategy to integrate these steps are significant for the construction of the system to predict a chemical's block of hERG current and also to predict the risk of inducing cardiac arrhythmias from the chemical information. The principles and criteria of elemental computations along this strategy are described.Key words: hERG, quantitative structure-activity relationship, molecular docking, Brownian dynamics simulation.Many ion channels and ion transporting systems contribute to the generation of the action potential of the heart. The ventricular action potential possesses a longlasting plateau that is terminated by the activation of repolarizing K + currents, I Kr and I Ks . The disturbance of these currents causes prolongation of the action potential duration and thus the QT interval of the electrocardiogram, and in many cases a worsening of transmural dispersion of repolarization [1][2][3]. These are the substrates for generation of life-threatening cardiac arrhythmias, including torsades de pointes. Many compounds inhibit I Kr , whose pore-forming subunit is the human ether-a-gogo-related gene (hERG) product. This can cause acquired forms of long QT syndrome [4][5][6]. The compounds exhibit a broad spectrum, including not only cardiac ion channel blockers, but also antipsychotic agents, antidepressant agents, antimicrobial agents, phosphodiesterase inhibitors, topoisomerase II inhibitors, and antagonists for G protein-coupled receptors, such as nonsedating antihistamine H 1 receptor blockers and β blockers [6]. The development of methods that could predict this phenomenon would improve the safety of pharmacological therapy and also facilitate the process of drug development.Here we propose an in silico str...

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Section: In Silico Prediction Systems For Chemical Block Of Hergsupporting

confidence: 90%

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

et al. 2008

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“…In 1992, Morgan and Sullivan published a pharmacophore model, based on a limited number of class III antiarrhythmic agents which are now known to preferentially block Kv11.1 channels (426). At the core of this pharmacophore lies a basic amine core attached by a short linker (1-4 atoms) to a phenyl ring.…”

Section: Herg K ϩ Channelsmentioning

confidence: 99%

hERG K⁺Channels: Structure, Function, and Clinical Significance

Vandenberg

Perry

Perrin

et al. 2012

Physiological Reviews

607

773

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The human ether-a-go-go related gene (hERG) encodes the pore-forming subunit of the rapid component of the delayed rectifier K(+) channel, Kv11.1, which are expressed in the heart, various brain regions, smooth muscle cells, endocrine cells, and a wide range of tumor cell lines. However, it is the role that Kv11.1 channels play in the heart that has been best characterized, for two main reasons. First, it is the gene product involved in chromosome 7-associated long QT syndrome (LQTS), an inherited disorder associated with a markedly increased risk of ventricular arrhythmias and sudden cardiac death. Second, blockade of Kv11.1, by a wide range of prescription medications, causes drug-induced QT prolongation with an increase in risk of sudden cardiac arrest. In the first part of this review, the properties of Kv11.1 channels, including biogenesis, trafficking, gating, and pharmacology are discussed, while the second part focuses on the pathophysiology of Kv11.1 channels.

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“…However, the absence of these receptors in the ventricle, and the lack of efficacy to produce similar effects by other more specific agonists of 5-HT 4 receptor, have ruled out this hypothesis [33]. Cisapride has class III antiarrhythmic properties [33][34] at slightly over therapeutic concentration (100 to 200 nmol/l,) whereas other prokinetic agents require very large concentration to show similar effect (metoclopramide, levosulpiride, mosapride, tegaserod, prucalopride, cinitapride) ( Table 1) [33][34][35][36][37][38][39][40][41][42]. This property can be attributed to the blockade of potassium currents, which increases the duration of the action potentials originating from cardiac muscle cells [3,41] like Class III antiarrhythmic agents [42,43].…”

Section: Mechanism Of Qt Prolongation By Proki-netic Agentsmentioning

confidence: 99%

Prokinetic Agents and QT Prolongation: A Familiar Scene with New Actors

Keller¹,

Girolamo²

2010

CDS

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Prokinetic agents are a very large family of drugs with different mechanisms of action. Only QT prolongation by cisapride has made notable impact and deserved its partial restriction and/or withdrawal from the market. Postmarketing surveillance initially showed that cisapride was generally safe and well tolerated, but in the past decade, more recent data have shown some risk in the patient populations. QT prolongation by prokinetic agents can raised from different mechanisms: some involve increased plasma concentrations of cisapride due to increased bioavailability by inhibiting P glycoprotein, and inhibition of metabolism or deficit in the elimination. On the other hand, pharmacodynamic interactions can also enhance the arrhythmogenic effect of cisapride. The present article presents the mechanisms and reviews the main interactions studied so far, and the role of pharmacovigilance in the detection of rare clinical events. We emphasize the need for physicians to look for conditions (either clinical or not) prone to increase the risk of QT interval prolongation.

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2 An Overview of Class III Electrophysiological Agents: A New Generation of Antiarrhythmic Therapy

Cited by 49 publications

References 131 publications

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

hERG K⁺Channels: Structure, Function, and Clinical Significance

Prokinetic Agents and QT Prolongation: A Familiar Scene with New Actors

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2 An Overview of Class III Electrophysiological Agents: A New Generation of Antiarrhythmic Therapy

Cited by 49 publications

References 131 publications

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

In Silico Prediction of the Chemical Block of Human Ether-a-Go-Go-Related Gene (hERG) K+ Current

hERG K+Channels: Structure, Function, and Clinical Significance

Prokinetic Agents and QT Prolongation: A Familiar Scene with New Actors

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Product

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hERG K⁺Channels: Structure, Function, and Clinical Significance