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

TY - JOUR

T1 - Molecular basis for class Ib anti-arrhythmic inhibition of cardiac sodium channels

AU - Pless, Stephan Alexander

AU - Galpin, Jason D

AU - Frankel, Adam

AU - Ahern, Christopher A

PY - 2011

Y1 - 2011

N2 - 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 cationĝ€"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.

AB - 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 cationĝ€"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.

KW - Anti-Arrhythmia Agents

KW - Arrhythmias, Cardiac

KW - Cations

KW - Electrophysiology

KW - Humans

KW - Models, Molecular

KW - Mutagenesis

KW - NAV1.5 Voltage-Gated Sodium Channel

KW - Patch-Clamp Techniques

KW - Phenylalanine

KW - Receptors, Drug

KW - Sodium Channel Blockers

KW - Sodium Channels

KW - Static Electricity

U2 - 10.1038/ncomms1351

DO - 10.1038/ncomms1351

M3 - Journal article

C2 - 21673672

SN - 2041-1723

VL - 2

SP - 351

JO - Nature Communications

JF - Nature Communications

ER -