Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656

@article{Scholz2007AnticholinergicAD,
  title={Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656},
  author={Eberhard P. Scholz and Franziska M. Konrad and Daniel L. Wei{\ss} and Edgar Zitron and Claudia Kiesecker and Ramona Bloehs and Martin Kulzer and Dierk Thomas and Sven Kathöfer and Alexander Bauer and Martin H. Maurer and Gunnar Seemann and Hugo A. Katus and Christoph Karle},
  journal={Naunyn-Schmiedeberg's Archives of Pharmacology},
  year={2007},
  volume={376},
  pages={275-284}
}
The anticholinergic antiparkinson drug orphenadrine is an antagonist at central and peripheral muscarinic receptors. Orphenadrine intake has recently been linked to QT prolongation and Torsade-de-Pointes tachycardia. So far, inhibitory effects on IKr or cloned HERG channels have not been examined. HERG channels were heterologously expressed in a HEK 293 cell line and in Xenopus oocytes and HERG current was measured using the whole cell patch clamp and the double electrode voltage clamp… 
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Background Citations
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Methods Citations
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13 Citations

Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action

It is shown that the anesthetic midazolam is a low-affinity inhibitor of cardiac hERG channels without additional effects on channel surface expression.

Involvement of voltage-gated sodium channels blockade in the analgesic effects of orphenadrine

Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action

Using the double-electrode voltage clamp technique, midazolam acted as a typical open-channel inhibitor with rapid onset of block and without frequency dependence of block, and is an open channel inhibitor of cardiac Kv1.5 channels.

Influence of orphenadrine upon the protective activity of various antiepileptics in the maximal electroshock-induced convulsions in mice.

Current pharmacogenomic studies on hERG potassium channels.

Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties

The main objective of this work was to collect and assess the hERG IC50 data available in accessible scientific literature to provide a high‐quality data set for further studies.

Predicting the potency of hERG K+ channel inhibition by combining 3D-QSAR pharmacophore and 2D-QSAR models

An ensemble of 3D-QSAR pharmacophore models was constructed to provide insight into the determinants of the interactions between the hERG K+ channel and channel inhibitors, and this final model outperformed any other individual model, showing the highest predictive ability and the lowest deviation.

Similarity-Based Classifier Using Topomers to Provide a Knowledge Base for hERG Channel Inhibition

It is shown that the similarity property principle can be applied to predict ADMET properties, exemplified on the case of hERG K+ channel inhibition, and is achievable for database sizes of about 10,000 structurally diverse molecules.

Identification of novel bioactive compounds from Olea europaea by evaluation of chemical compounds in the OliveNet™ library: in silico bioactivity and molecular modelling, and in vitro validation of hERG activity

hERG in vitro interchange factors—development and verification

The main objective of this work was to develop the extrapolation factors allowing inter-system (HEK, CHO, XO) and inter-temperature (room and physiological) IC50 values comparison based on the collected and analyzed hERG IC50 data.

References

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The antipsychotic drug chlorpromazine inhibits HERG potassium channels

Analysis of the voltage dependence of block revealed a reduction of inhibition at positive membrane potentials, andhibition of HERG channels by chlorpromazine displayed reverse frequency dependence, that is, the amount of block was lower at higher stimulation rates.

Drug binding to aromatic residues in the HERG channel pore cavity as possible explanation for acquired Long QT syndrome by antiparkinsonian drug budipine

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It is shown that halofantrine preferentially blocks open and inactivated HERG channels heterologously expressed in Xenopus laevis oocytes and requires channels to open before it can gain access to its binding site located in the central cavity of the HERG channel.

The antidepressant drug fluoxetine is an inhibitor of human ether-a-go-go-related gene (HERG) potassium channels.

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A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel

MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia