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

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. H...

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Main Authors: Scholz, Eberhard P. (Author) , Konrad, Franziska Magdalena (Author) , Weiss, Daniel L. (Author) , Zitron, Edgar (Author) , Seyler, Claudia (Author) , Bloehs, Ramona (Author) , Kulzer, Martin (Author) , Thomas, Dierk (Author) , Kathöfer, Sven (Author) , Bauer, Alexander (Author) , Maurer, Martin H. (Author) , Seemann, Gunnar (Author) , Katus, Hugo (Author) , Karle, Christoph (Author)
Format: Article (Journal)
Language:English
Published: 27 October 2007
In: Naunyn-Schmiedeberg's archives of pharmacology
Year: 2007, Volume: 376, Issue: 4, Pages: 275-284
ISSN:1432-1912
DOI:10.1007/s00210-007-0202-6
Online Access:Resolving-System, lizenzpflichtig, Volltext: https://doi.org/10.1007/s00210-007-0202-6
Verlag, lizenzpflichtig, Volltext: https://link.springer.com/article/10.1007/s00210-007-0202-6
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Author Notes:Eberhard P. Scholz, Franziska M. Konrad, Daniel L. Weiss, Edgar Zitron, Claudia Kiesecker, Ramona Bloehs, Martin Kulzer, Dierk Thomas, Sven Kathöfer, Alexander Bauer, Martin H. Maurer, Gunnar Seemann, Hugo A. Katus, Christoph A. Karle
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Summary: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 technique. Orphenadrine inhibits cloned HERG channels in a concentration dependent manner, yielding an IC50 of 0.85 μM in HEK cells. Onset of block is fast and reversible upon washout. Orphenadrine does not alter the half-maximal activation voltage of HERG channels. There is no shift of the half-maximal steady-state-inactivation voltage. Time constants of direct channel inactivation are not altered significantly and there is no use-dependence of block. HERG blockade is attenuated significantly in mutant channels lacking either of the aromatic pore residues Y652 and F656. In conclusion, we show that the anticholinergic agent orphenadrine is an antagonist at HERG channels. These results provide a novel molecular basis for the reported proarrhythmic side effects of orphenadrine.
Item Description:Gesehen am 13.01.2025
Physical Description:Online Resource
ISSN:1432-1912
DOI:10.1007/s00210-007-0202-6

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