Volume 7 Supplement 2

13th Scientific Symposium of the Austrian Pharmacological Society (APHAR). Joint Meeting with the Austrian Society of Toxicology (ASTOX) and the Hungarian Society for Experimental and Clinical Pharmacology (MFT)

Open Access

Exploring the heterogeneity of use-dependent sodium channel inhibitor drugs. I: Fast- vs. slow-inactivated state preference

  • Nora Lenkey1,
  • Robert Karoly1,
  • E Sylvester Vizi1 and
  • Arpad Mike1Email author
BMC Pharmacology20077(Suppl 2):A41

DOI: 10.1186/1471-2210-7-S2-A41

Published: 14 November 2007

Certain drugs evidently exert their therapeutic effects via sodium channel inhibition: local anesthetics, class I antiarrhythmics and certain anticonvulsants. Novel sodium channel inhibitor compounds are actively investigated for other indications involving stroke, ischemia, various neurodegenerative conditions and pain syndromes. All these drugs cause voltage- and use-dependent inhibition of sodium channels. However, biophysical properties of inhibition can differ widely even between use-dependent sodium channel inhibitors which seem to act similarly. Recently it has been proposed that the mechanism of inhibition can be more important than potency or isoform selectivity regarding the therapeutical potential of the drugs (e.g. [1]). One important question is which conformational state is preferred by the drug. In this study we attempted to discriminate preference to fast- vs. slow-inactivated conformations. Slow association to fast-inactivated state and fast association to slow-inactivated state cannot be distinguished using traditional protocols. We have recently developed a protocol to test fast- vs. slow-inactivated state preference using electrophysiology only, i.e. without mutagenesis or enzymatic treatment experiments. We tested 28 use-dependent sodium channel inhibitors of different chemical structure and therapeutic indication using this protocol, and found that the mechanisms primarily overlap with the latter.

Authors’ Affiliations

(1)
Institute of Experimental Medicine

References

  1. Ilyin VI, Pomonis JD, Whiteside GT, Harrison JE, Pearson MS, Mark L, Turchin PI, Gottshall S, Carter RB, Nguyen P, Hogenkamp DJ, Olanrewaju S, Benjamin E, Woodward RM: Pharmacology of 2-[4-(4-chloro-2-fluorophenoxy)phenyl]-pyrimidine-4-carboxamide: A potent, broad-spectrum state-dependent sodium channel blocker for treating pain states. J Pharmacol Exp Ther. 2006, 318: 1083-1093. 10.1124/jpet.106.104737.View ArticlePubMedGoogle Scholar

Copyright

© Lenkey et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

Advertisement