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A Novel Drug Binding Site on Voltage-Gated Sodium Channels in Rat Brain

Wolfson Institute for Biomedical Research, University College London, London United Kingdom (D.R.R., J.G.); and School of Science and School of Pharmacy, University of Greenwich at Medway, Chatham Maritime, United Kingdom (M.J.L.)

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.

Address correspondence to: Dr. John Garthwaite, Wolfson Institute for Biomedical Research, University College London, Gower St., London WC1E 6BT, UK. E-mail: john.garthwaite{at}ucl.ac.uk

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