Mátyás C Földi1,2, Krisztina Pesti1,3,4, Katalin Zboray2, Adam V Toth2, Tamás Hegedűs5, András Málnási-Csizmadia6, Peter Lukacs1,2, Arpad Mike1,2,3. 1. MTA-ELTE NAP B Opto-Neuropharmacology Group, Budapest, Hungary. 2. Plant Protection Institute, Centre for Agricultural Research, Martonvásár, Hungary. 3. Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary. 4. School of PhD Studies, Semmelweis University, Budapest, Hungary. 5. Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary. 6. Motor Pharmacology Research Group, Department of Biochemistry, Eötvös Loránd University, Budapest, Hungary.
Abstract
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.
BACKGROUND AND PURPOSE: 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. EXPERIMENTAL APPROACH: 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. KEY RESULTS: 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. CONCLUSIONS AND IMPLICATIONS: 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.
Authors: Benjamin Hackl; Peter Lukacs; Janine Ebner; Krisztina Pesti; Nicholas Haechl; Mátyás C Földi; Elena Lilliu; Klaus Schicker; Helmut Kubista; Anna Stary-Weinzinger; Karlheinz Hilber; Arpad Mike; Hannes Todt; Xaver Koenig Journal: Front Pharmacol Date: 2022-05-02 Impact factor: 5.988