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A novel drug binding site on voltage-gated sodium channels in rat brain

A novel drug binding site on voltage-gated sodium channels in rat brain

Riddall, Dieter R., Leach, Michael J. ORCID: 0000-0002-9859-1325 and Garthwaite, John (2006) A novel drug binding site on voltage-gated sodium channels in rat brain. Molecular Pharmacology, 69 (1). pp. 278-287. ISSN 1521-0111 (Online) (doi:

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The effectiveness of several antiepileptic, analgesic, and neuroprotective drugs is attributable to state-dependent inhibition of voltage-gated sodium channels. To help characterize their site and mode of action on sodium channels, a member of the lamotrigine family, R-(�)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)- pyrimidine (BW202W92), was radiolabeled and used as a binding ligand in rat forebrain synaptosomes. Although the level of specific [3H]BW202W92 binding in a standard incubation medium was relatively poor, low concentrations of tetrodotoxin (EC50 � 2–3 nM) greatly enhanced the binding, apparently by increasing the affinity of the binding sites. Tetrodotoxin-dependent binding was stereoselective (the less active enantiomer, S-(�)-2,4-diamino-6-(fluromethyl)-5-(2,3,5-trichlorophenyl)- pyrimidine (BW203W92), was up to 30-fold less potent, depending on conditions) and was extremely sensitive to inhibition by raised K� concentration (IC50 � 5.9 mM), an effect that was ascribed to changes in membrane potential. In addition, the binding was inhibited by sodium channel neurotoxins acting on sites 3 and 4, but it was resistant to batrachotoxin (site 2) and brevetoxin (site 5). Several drugs acting on sodium channels displaced tetrodotoxin-dependent [3H]BW202W92 binding, and most of those tested showed different affinities under depolarized (100 mM K�) and polarized (1 mM K�) conditions. In a subset of compounds for which data were available, binding affinity in depolarized synaptosomes correlated well with apparent affinity for the inactivated state of sodium channels. The [3H]BW202W92 binding site is novel and is likely to represent a pharmacologically important site of action of drugs on voltage-gated sodium channels in the brain.

Item Type: Article
Additional Information: [1] Published online before print October 11, 2005.
Uncontrolled Keywords: voltage-gated sodium channels, binding site, BW202W92
Subjects: Q Science > QR Microbiology
Faculty / School / Research Centre / Research Group: Faculty of Education, Health & Human Sciences > School of Human Sciences (HUM)
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Last Modified: 09 Oct 2021 04:46

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