Voltage-Gated Sodium Channel Modulation by Mexiletine Analogues

AUTHORS:

Phillipe de Lima Rosado Santos

Victória Gabriela Bello-Santos

Newton Gonçalves Castro

AFFILIATION:

Laboratório de Farmacologia Molecular, Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro

Voltage-gated sodium channels (VGSC) are essential for the rapid conduction of information in the CNS and also in non-neural cell excitability. They are important therapeutic targets of pharmacological modulators and their abnormal functioning generates conditions known as “channelopathies”. Modulation of VGSC function must be extremely delicate, because small changes in the activation, inactivation or refractoriness of these ion channels can generate major physiological effects. Due to the subtlety required to appropriately modulate VGSC according to clinical demand, the availability of a wide range of modulating tools becomes crucial. Mexiletine is an orally active VGSC inhibitor whose specific properties are useful in controlling certain types of cardiac arrhythmia, but which has also been proposed for use in pain and neurological conditions. In collaboration with groups from FIOCRUZ, we are investigating novel compounds structurally related to mexiletine. We used the patch clamp technique to characterize the effects of compounds on amplitude and voltage-dependent kinetics of VGSC currents in the GH3 cell line, which expresses the main subtypes of neural VGSC. We have identified a novel potent and state-dependent VGSC inhibitor, which showed an IC50 of 28.3 microM for tonic block, prolonged channel inactivation and shifted its voltage-dependence. Further in-depth analysis of the modulating effects of this compound and its positional isomers will contribute to the characterization of the structure-activity relationship of VGSC modulators, generating an understanding of how this modulation occurs and aiding in the rational design and synthesis of new candidate therapeutic agents.