A Comparative Automated Electrophysiology Study of 43 Sodium Channel Inhibitors. Distinct Types of Inhibition Correlate with Chemical Properties of Drugs

A comparative electrophysiological study of 43 drugs was carried out using rNav1.2 expressing HEK 293 cells and the QPatch automatic patch-clamp instrument. IC50 values were calculated for all drugs, and for the 35 drugs which caused substantial inhibition of sodium channels, onset/offset kinetics, reversibility and use-dependence were also determined. Based on these properties, sodium channel inhibitor drugs could be classified into distinct types. We have observed that properties of inhibition correlated with chemical properties, and that categories based on properties of inhibition often concurred with therapeutic categories. For example, a subset of antidepressants (tricyclic compounds and selective serotonin reuptake inhibitors) inhibited sodium channels in a special way (with high affinity, slow kinetics, poor reversibility and use dependence), which was clearly different from the inhibition caused by classic sodium channel inhibitors (low affinity, fast kinetics, and good reversibility). Recording multiple properties of inhibition did not make our measurements more costly or time consuming, but provided additional information. By the help of this extra information, we have established that sodium channel inhibitors are heterogeneous, delineated specific types of inhibition, and observed correlations both with chemical properties and therapeutic profile that would be hidden if the IC50 alone was determined.