Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

Stephan A. Pless, Jason D. Galpin, Adam Frankel and Christopher A. Ahern ()
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Stephan A. Pless: Pharmacology and Therapeutics and Cellular and Physiological Sciences, University of British Columbia
Jason D. Galpin: Faculty of Pharmaceutical Sciences, University of British Columbia
Adam Frankel: Faculty of Pharmaceutical Sciences, University of British Columbia
Christopher A. Ahern: Pharmacology and Therapeutics and Cellular and Physiological Sciences, University of British Columbia

Nature Communications, 2011, vol. 2, issue 1, 1-9

Abstract: Abstract Cardiac sodium channels are established therapeutic targets for the management of inherited and acquired arrhythmias by class I anti-arrhythmic drugs (AADs). These drugs share a common target receptor bearing two highly conserved aromatic side chains, and are subdivided by the Vaughan-Williams classification system into classes Ia-c based on their distinct effects on the electrocardiogram. How can these drugs elicit distinct effects on the cardiac action potential by binding to a common receptor? Here we use fluorinated phenylalanine derivatives to test whether the electronegative surface potential of aromatic side chains contributes to inhibition by six class I AADs. Surprisingly, we find that class Ib AADs bind via a strong electrostatic cation–pi interaction, whereas class Ia and Ic AADs rely significantly less on this interaction. Our data shed new light on drug-target interactions underlying the inhibition of cardiac sodium channels by clinically relevant drugs and provide information for the directed design of AADs.

Date: 2011
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DOI: 10.1038/ncomms1351

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