Sodium channel inhibitors can be used to treat hyperexcitability-related diseases,
including epilepsies, pain syndromes, neuromuscular disorders, and cardiac arrhythmias.
The applicability of these drugs is limited by their nonspecific effect on physiological
function. They act mainly by sodium channel block and in addition by modulation of
channel kinetics. While channel block inhibits healthy and pathological tissue equally,
modulation can preferentially inhibit pathological activity. An ideal drug designed
to target the sodium channels of pathological tissue would act predominantly by modulation.
Thus far, no such drug has been described.Patch-clamp experiments with ultra-fast
solution exchange and photolabeling-coupled electrophysiology were applied to describe
the unique mechanism of riluzole on Nav1.4 sodium channels. In silico docking experiments
were used to study the molecular details of binding.We present evidence that riluzole
acts predominantly by non-blocking modulation. We propose that, being a relatively
small molecule, riluzole is able to stay bound to the binding site, but nonetheless
stay off the conduction pathway, by residing in one of the fenestrations. We demonstrate
how this mechanism can be recognized.Our results identify riluzole as the prototype
of this new class of sodium channel inhibitors. Drugs of this class are expected to
selectively prevent hyperexcitability, while having minimal effect on cells firing
at a normal rate from a normal resting potential.