Phenytoin Derivatives as Antagonists of AMPA Receptors and Voltage-Gated Sodium Channels: A Structure-Function Study

The development of antiepileptic drugs remains a serious challenge for both academia and industry. Ionotropic glutamate receptors and voltage-gated sodium channels are among the primary targets of antiepileptic agents. Recent studies have revealed a unique property of phenytoin: unlike other sodium-channel blockers, it inhibits calcium-impermeable AMPA receptors at micromolar concentrations. In this study, we explored the structure-activity relationships of eight phenytoin derivatives. The effects of the compounds on neuronal voltage-gated Na⁺ channels and neuronal AMPA receptor channels were examined using the patch-clamp technique. For the Na⁺ channels, we analyzed tonic block, shifts of steady-state inactivation, and frequency-dependent block. For the AMPA receptors, we investigated kinetics, agonist dependence, and trapping effects. NH groups at positions 1 and 3, the carbonyl groups at positions 2 and 4, and the phenyl group at position 5 are important, since their replacement causes a decrease in activity. Replacement of oxygen with sulfur at position 2 results in a significant increase in activity on both types of channels. For the AMPA receptor, this increase is attributable to a more stable drug-channel complex. The enhanced action on sodium channels is due to an increase in tonic block, whereas the effects on inactivated and open channels remain unchanged. These results suggest a new possibility for tuning the activities of phenytoin derivatives against both primary targets to obtain anticonvulsants with novel properties.