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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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

This is the first study that provides a molecular basis for the budipine-associated aLQTS observed in clinical practice and underline the importance of the aromatic residues Y652 and F656 in the binding of lipophilic drugs to HERG channels.

Class Ia anti-arrhythmic drug ajmaline blocks HERG potassium channels: mode of action

In conclusion, inhibitory effects on HERG channels may contribute to both the high anti-arrhythmic efficacy of ajmaline and to its pro-arrHythmic potential.

Orphenadrine is an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist: binding and patch clamp studies

It is shown that orphenadrine inhibits [3H]MK-801 binding to the phencyclidine (PCP) binding site of the N-methyl-D-aspartate (NMDA)-receptor in homogenates of postmortem human frontal cortex with a Ki-value of 6.0 ± 0.7 μM.

Inhibition of cardiac HERG currents by the DNA topoisomerase II inhibitor amsacrine: mode of action

Data demonstrate that the anticancer drug amsacrine is an antagonist of cloned HERG potassium channels, providing a molecular mechanism for the previously reported QTc interval prolongation during clinical administration of amSacrine.

Inhibition of cardiac HERG channels by grapefruit flavonoid naringenin: implications for the influence of dietary compounds on cardiac repolarisation

The electrophysiological properties of HERG blockade by naringenin were analysed and it was observed that grapefruit juice induced mild QTc prolongation in healthy subjects and may have important implications for phytotherapy and for dietary recommendations for cardiologic patients.

Block of wild-type and inactivation-deficient human ether-a-go-go-related gene K+ channels by halofantrine

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.

This is the first study demonstrating that HERG potassium channels are blocked by the selective serotonin reuptake inhibitor fluoxetine, and it is concluded that HerG current inhibition might be an explanation for the arrhythmogenic side effects of this drug.