ArticleMolecular pharmacology2010
Molecular model of anticonvulsant drug binding to the voltage-gated sodium channel inner pore.
Article in Molecular pharmacology, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 50 papers.
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Who cites it
50 citing papers in PubMed, 111 citations in OpenAlex.
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- An In Vivo and In Silico Approach Reveals Possible Sodium Channel Nav1.2 Inhibitors fromBrain sciences · 2024Article
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- Frontline Sodium Channel-Blocking Antiseizure Medicine Use Promotes Future Onset of Drug-Resistant Chronic Seizures.International journal of molecular sciences · 2023Article
- From HDAC to Voltage-Gated Ion Channels: What's Next? The Long Road of Antiepileptic Drugs Repositioning in Cancer.Cancers · 2022Review
- Effects of Antiarrhythmic Drugs on Antiepileptic Drug Action-A Critical Review of Experimental Findings.International journal of molecular sciences · 2022Review
- Differences in local anaesthetic and antiepileptic binding in the inactivated state of human sodium channel Nav1.4.Biophysical journal · 2021Article
- SCN8A Encephalopathy: Case Report and Literature Review.Neurology international · 2021Article
- Lacosamide Inhibition of NaFrontiers in pharmacology · 2021Article
- Development of Allosteric Modulators of Voltage-Gated NaCurrent topics in medicinal chemistry · 2021Review
- Variant-specific changes in persistent or resurgent sodium current in SCN8A-related epilepsy patient-derived neurons.Brain : a journal of neurology · 2020Article
- Lack of Association of Generic Brittle Status with Genetics and Physiologic Measures in Patients with Epilepsy.Pharmaceutical research · 2020Article
- Inhibitory Effect of Eslicarbazepine Acetate and S-Licarbazepine on NaFrontiers in pharmacology · 2020Article
- Synthesis and biological activities of local anesthetics.RSC advances · 2019Review
- Article
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
The tricyclic anticonvulsant drugs phenytoin, carbamazepine, and lamotrigine block neuronal voltage-gated Na(+) channels, and their binding sites to domain IV-S6 in the channel's inner pore overlap with those of local anesthetic drugs. These anticonvulsants are neutral, in contrast to the mostly positively charged local anesthetics, but their open/inactivated-state blocking affinities are similar. Using a model of the open pore of the Na(+) channel that we developed by homology with the crystal structures of potassium channels, we have docked these three anticonvulsants with residues identified by mutagenesis as important for their binding energy. The three drugs show a common pharmacophore, including an aromatic ring that has an aromatic-aromatic interaction with Tyr-1771 of Na(V)1.2 and a polar amide or imide that interacts with the aromatic ring of Phe-1764 by a low-energy amino-aromatic hydrogen bond. The second aromatic ring is nearly at a right angle to the pharmacophore and fills the pore lumen, probably interacting with the other S6 segments and physically occluding the inner pore to block Na(+) permeation. Hydrophobic interactions with this second aromatic ring may contribute an important component to binding for anticonvulsants, which compensates energetically for the absence of positive charge in their structures. Voltage dependence of block, their important therapeutic property, results from their interaction with Phe-1764, which connects them to the voltage sensors. Their use dependence is modest and this results from being neutral, with a fast drug off-rate after repolarization, allowing a normal action potential rate in the presence of the drugs.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.