A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs

Kongsamut, Sathapana; Kang, Jiesheng; Chen, Xiaoliang; Roehr, Joachim E.; Rampe, David

doi:10.1016/s0014-2999(02)02074-5

Cited by 217 publications

(130 citation statements)

References 20 publications

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“…PPB are either from published data (plain text) or measured in our laboratories (bold italics). [22]; c: [23]; d: [24,25]; e: [26]; f: [27]; g: [28]; h: [19]; i: [29]; j: [30]; k: [31]; l: [32]; m: [33]; n: [34]; o: [35]; p: [36]; q: [37]; r: [38]; s: [39]; t: [40]; u: [41]; v: [42]; w: [43]; x: [44]; y: [45]; z: [46]; aa: [47]; bb: [48]; cc: [49]; dd: [50]; ee: [51]; ff: [52]; gg: [53]; hh: [54]; ii: [55]; jj: [56]; kk: [57]; ll: [58]; mm: [59]; nn: [60]; oo: [61]; pp: [62]; qq: [63]; rr: [64]; ss: [65]; tt: [66]; uu: [67]; vv: [68]; ww: …”

Section: Drugs With a Cardiovascular Target Without A Direct Role In mentioning

confidence: 99%

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Sube¹,

Ertel²

2017

JBiSE

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Introduction: Cardiomyocytes derived from human induced pluripotent stem cells (hiPSC-CM) form spontaneously beating syncytia in-vitro. We evaluated whether hiPSC-CM are a compelling model of human cardiac pharmacology useful for early drug development. Methods: We measured hiPSC-CM beating frequency using Ca-sensitive dyes and a high-throughput screening system. We quantified the effects of 640 drugs with various structures and pharmacologies. Results: When tested at 1 µM, most drugs without direct effects on heart rhythm or with effects at high concentrations do not change frequency, indicating specificity. In contrast, the preparation detects compounds with direct activity on heart rhythm, demonstrating sensitivity. In particular, β-adrenergic agonists increase frequency and the model differentiates β2 from β1 agonists, as well as partial from full agonists. Phosphodiesterase inhibitors have subtype-specific actions and PDE4 is particularly important in controlling frequency. The preparation is sensitive to cardiac ion channel blockers: L-type calcium channel blockers, Class-I and Class-III antiarrhythmics change frequency but drugs acting on K ATP channels do not. The assay detects compounds blocking the cardiac rapid delayed-rectifier K channel and is an alternative to the classic "hERG test".Conclusion: hiPSC-CM are a useful in-vitro cardiac model in drug development since they respond appropriately to drugs that modify heart rate in humans.

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Section: Drugs With a Cardiovascular Target Without A Direct Role In mentioning

confidence: 99%

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Sube¹,

Ertel²

2017

JBiSE

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“…Thioridazine was reported to prolong the QTcB interval after a single oral dose of 50 mg / kg (34), prolong the APD in guinea pigs (15), and to block hERG currents (35). Thioridazine prolonged the QTcB interval to 14% at the middle dose.…”

Section: Predictability Of Qtcb Prolongation In Cynomolgus Monkeymentioning

confidence: 99%

QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

Ando

Hombo

Kanno³

et al. 2005

J Pharmacol Sci

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Abstract. In safety pharmacology studies, the effects on the QT interval of electrocardiograms are routinely assessed using a telemetry system in cynomolgus monkeys. However, there is a lack of integrated databases concerning in vivo QT assays in conscious monkeys. As part of QT Interval Prolongation: Project for Database Construction (QT PRODACT), the present study examined 10 positive compounds with the potential to prolong the QT interval and 6 negative compounds considered to have no such effect on humans. The experiments were conducted at 7 facilities in accordance with a standard protocol established by QT PRODACT. The vehicle or 3 doses of each test compound were administered orally to male cynomolgus monkeys (n = 3 -4), and telemetry signals were recorded for 24 h. None of the negative compounds prolonged the corrected QT using Bazett's formula (QTcB) interval. On the other hand, almost all of the positive compounds prolonged the QTcB interval, but haloperidol, terfenadine, and thioridazine did not. The failure to detect the QTcB interval prolongation appeared to be attributable for the differences in metabolism between species and / or disagreement with Bazett's formula for tachycardia. In the cynomolgus monkeys, astemizole induced Torsade de Pointes and cisapride caused tachyarrhythmia at lower plasma concentrations than those observed in humans and dogs. These results suggest that in vivo QT assays in conscious monkeys represent a useful model for assessing the risks of drug-induced QT interval prolongation. Supplementary material (Appendix): available only at http://dx

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“…Diverse conformations of each chemical were generated, and conformations whose energy was less than 20 kcal/mol compared to the most stable conformer were [108] and budipine (0.85 µM) [129] measured with isolated ventricular myocytes from either rabbit or guinea pig were also included in the data set. [41], sertindole [39], thioridazine [39], loratadine [40], and mizolastine [19], were predicted based on the 3D-QSAR (closed circles).…”

Section: Strategy For the Prediction Of Inhibitory Activity Of Compoumentioning

confidence: 99%

“…Anti-psychotic drugs (thioridazine (IC 50 ; 0.191 µM) [39] and sertindole (0.003 µM) [39]), anti-histamine H 1 R antagonists (mizolastine (8.9 µM) [19] and loratadine (4.0 µM) [40]), and the Ca 2+ channel blocker (mibefradil (1.43 µM) [41]) were examined ( Fig. 2Bb closed circles).…”

Section: In Silico Prediction Systems For Chemical Block Of Hergmentioning

confidence: 99%

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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A comparison of the receptor binding and HERG channel affinities for a series of antipsychotic drugs

Cited by 217 publications

References 20 publications

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

Cardiomyocytes Derived from Human Induced Pluripotent Stem Cells: An In-Vitro Model to Predict Cardiac Effects of Drugs

QT PRODACT: In Vivo QT Assay With a Conscious Monkey for Assessment of the Potential for Drug-Induced QT Interval Prolongation

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

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