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Research ArticleArticle

Molecular Model of Anticonvulsant Drug Binding to the Voltage-Gated Sodium Channel Inner Pore

Gregory M. Lipkind and Harry A. Fozzard
Molecular Pharmacology October 2010, 78 (4) 631-638; DOI: https://doi.org/10.1124/mol.110.064683
Gregory M. Lipkind
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Harry A. Fozzard
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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 NaV1.2 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.

Footnotes

  • This work was supported by the National Institutes of Health National Heart, Blood, and Lung Institute [Grant HL065661].

  • Article, publication date, and citation information can be found at http://molpharm.aspetjournals.org.

    doi:10.1124/mol.110.064683.

  • ABBREVIATIONS:

    Nav1.2
    one of the three brain isoforms of the Na+ channel
    KcsA and MthK
    two isoforms of the potassium channel
    S6
    the sixth transmembrane helix of a domain of the Na channel.

  • Received March 12, 2010.
  • Accepted July 19, 2010.
  • Copyright © 2010 The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 78 (4)
Molecular Pharmacology
Vol. 78, Issue 4
1 Oct 2010
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Research ArticleArticle

Molecular Model of Anticonvulsant Drug Binding to the Voltage-Gated Sodium Channel Inner Pore

Gregory M. Lipkind and Harry A. Fozzard
Molecular Pharmacology October 1, 2010, 78 (4) 631-638; DOI: https://doi.org/10.1124/mol.110.064683

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Research ArticleArticle

Molecular Model of Anticonvulsant Drug Binding to the Voltage-Gated Sodium Channel Inner Pore

Gregory M. Lipkind and Harry A. Fozzard
Molecular Pharmacology October 1, 2010, 78 (4) 631-638; DOI: https://doi.org/10.1124/mol.110.064683
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