ArticleNaunyn-Schmiedeberg's archives of pharmacology2007
Anticholinergic antiparkinson drug orphenadrine inhibits HERG channels: block attenuation by mutations of the pore residues Y652 or F656.
Article in Naunyn-Schmiedeberg's archives of pharmacology, 2007. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
4 citing papers in PubMed, 13 citations in OpenAlex.
- Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action.Drug design, development and therapy · 2015Article
- Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action.Drug design, development and therapy · 2014Article
- Acute and subacute effects of the selective serotonin-noradrenaline reuptake inhibitor duloxetine on cardiac hERG channels.Naunyn-Schmiedeberg's archives of pharmacology · 2013Article
- Predicting the potency of hERG K⁺ channel inhibition by combining 3D-QSAR pharmacophore and 2D-QSAR models.Journal of molecular modeling · 2012Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
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 I (Kr) 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 IC(50) of 0.85 microM 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.
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