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

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


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Arrhythmia Agents / classification
  • Anti-Arrhythmia Agents / pharmacology*
  • Arrhythmias, Cardiac / drug therapy*
  • Cations / metabolism
  • Electrophysiology
  • Humans
  • Models, Molecular*
  • Mutagenesis
  • NAV1.5 Voltage-Gated Sodium Channel
  • Patch-Clamp Techniques
  • Phenylalanine
  • Receptors, Drug / metabolism*
  • Sodium Channel Blockers / pharmacology*
  • Sodium Channels / chemistry
  • Sodium Channels / genetics
  • Sodium Channels / metabolism*
  • Static Electricity


  • Anti-Arrhythmia Agents
  • Cations
  • NAV1.5 Voltage-Gated Sodium Channel
  • Receptors, Drug
  • SCN5A protein, human
  • Sodium Channel Blockers
  • Sodium Channels
  • Phenylalanine