Inhibition of neuronal Na⁺ currents by lacosamide: Differential binding affinity and kinetics to different inactivated states

Lacosamide is a new-generation anticonvulsant acting on Na⁺ channels. Compared to the classic anticonvulsants targeting Na⁺ channels, lacosamide is unique in structure and in its molecular action requiring longer membrane depolarization. Selective binding to the slow inactivated state of Na⁺ channels was then advocated for lacosamide, although slow binding to the fast inactivated state was alternatively proposed recently. In addition, quantitative characterization of lacosamide action has been deficient. We investigated the interactions between lacosamide and Na⁺ channels in native mammalian neurons, and found that the apparent dissociation constant (~13.7 μM) of lacosamide to the slow inactivated state is well within the therapeutic concentration range and is much (>15-fold) lower than the dissociation constant of lacosamide to the fast inactivated state. Besides, lacosamide has extremely slow binding rates (<400 M⁻¹sec⁻¹) to the fast but much faster binding rates (>3000 M⁻¹sec⁻¹) to the slow inactivated Na⁺ channels. Consistent with these biophysical characters, we further demonstrated that lacosamide is much more effective against the repetitive burst discharges with interburst intervals at −60 mV than −80 mV. With preponderant binding to the slow inactivation state in therapeutic concentrations and thus less propensity to affect normal discharges, lacosamide could be a drug of choice for seizure discharges characterized by relatively depolarized interburst intervals, during which more slow inactivated states could be generated and more binding of lacosamide would ensue.