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Nat Commun. 2011 Jun 14;2:351. doi: 10.1038/ncomms1351.

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

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Department of Anesthesiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia, V6T 1Z3 Canada.


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.

[Indexed for MEDLINE]

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