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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Anesthetic drug midazolam inhibits cardiac human ether-à-go-go-related gene channels: mode of action
TLDR
It is shown that the anesthetic midazolam is a low-affinity inhibitor of cardiac hERG channels without additional effects on channel surface expression.
Acute and subacute effects of the selective serotonin–noradrenaline reuptake inhibitor duloxetine on cardiac hERG channels
TLDR
Whereas inhibitory effects of duloxetine seem negligible under therapeutically relevant concentrations, hERG block should be considered in cases of dULoxetines overdose and when administering dulxetine to patients susceptible to drug-induced QT prolongation.
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TLDR
Orphenadrine affinities for resting and inactivated sodium channels were higher compared to those of known sodium channels blockers, such as mexiletine and flecainide, indicating a role for sodium channel blockade in the clinical efficacy of or phenadrine as analgesic compound.
Inhibition of cardiac Kv1.5 potassium current by the anesthetic midazolam: mode of action
TLDR
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.
TLDR
Orphenadrine failed to enhance the protective activity of carbamazepine, phenytoin, phenobarbital, lamotrigine, topiramate, or oxcarbazepine against maximal electroshock-induced seizures and significantly enhanced the anticonvulsant activity of valproate.
Current pharmacogenomic studies on hERG potassium channels.
TLDR
Current pharmacogenomic studies on hERG potassium channels are reviewed to provide a reference for developing individualized treatments and evaluating their safety, and detecting polymorphisms in KCNH2 encoding hERG1 is of great significance in guiding the prevention and treatment of related diseases.
Collation, assessment and analysis of literature in vitro data on hERG receptor blocking potency for subsequent modeling of drugs' cardiotoxic properties
TLDR
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.
Orphenadrine induces secondarily generalized convulsive status epilepticus in rats
The current study was aimed to assess the convulsant potency of orphenadrine (ORPH) in rats together with a screen of different conventional antiepileptic drugs (AEDs) on their efficacy to suppress…
Predicting the potency of hERG K+ channel inhibition by combining 3D-QSAR pharmacophore and 2D-QSAR models
TLDR
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
TLDR
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.
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References

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TLDR
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
TLDR
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.
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TLDR
In conclusion, inhibitory effects on HERG channels may contribute to both the high anti-arrhythmic efficacy of ajmaline and to its pro-arrHythmic potential.
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
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TLDR
The finding that HERG encodes IKr channels provides a mechanistic link between certain forms of inherited and acquired LQT, and that an additional subunit may be required for drug sensitivity.
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TLDR
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