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

  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},
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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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

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

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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.

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