Non-blocking modulation contributes to sodium channel inhibition by a covalently attached photoreactive riluzole analog
Sodium channel inhibitor drugs decrease pathological hyperactivity in various diseases including pain syndromes, myotonia, arrhythmias, nerve injuries and epilepsies. Inhibiting pathological but not physiological activity, however, is a major challenge in drug development. Sodium channel inhibitors exert their efects by a dual action: they obstruct ion fow (“block”), and they alter the energetics of channel opening and closing (“modulation”). Ideal drugs would be modulators without blocking efect, because modulation is inherently activity-dependent, therefore selective for pathological hyperactivity. Can block and modulation be separated? It has been difcult to tell, because the efect of modulation is obscured by conformation-dependent association/dissociation of the drug. To eliminate dynamic association/dissociation, we used a photoreactive riluzole analog which could be covalently bound to the channel; and found, unexpectedly, that drug-bound channels could still conduct ions, although with modulated gating. The fnding that non-blocking modulation is possible, may open a novel avenue for drug development because non-blocking modulators could be more specifc in treating hyperactivity-linked diseases.