title: Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels.
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.
authors.affiliation: Department of Anesthesiology, University of British Columbia, 2350 Health Science Mall, Vancouver, British Columbia, V6T 1Z3 Canada.
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Pless
authors.forename: Jason D
authors.initials: JD
authors.lastname: Galpin
authors.forename: Adam
authors.initials: A
authors.lastname: Frankel
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Ahern
mesh_terms: D000889:Anti-Arrhythmia Agents / Q000145:classification / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000188:drug therapy*; D002412:Cations / Q000378:metabolism; D004594:Electrophysiology; D006801:Humans; D008958:Models, Molecular; D016296:Mutagenesis; D062554:NAV1.5 Voltage-Gated Sodium Channel; D018408:Patch-Clamp Techniques; D010649:Phenylalanine; D011955:Receptors, Drug / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology*; D015222:Sodium Channels / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055672:Static Electricity
chemical_list: D000889:Anti-Arrhythmia Agents; D002412:Cations; D062554:NAV1.5 Voltage-Gated Sodium Channel; D011955:Receptors, Drug; C568320:SCN5A protein, human; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D010649:Phenylalanine