Nils Damann

Advances in targeting voltage-gated sodium channels with small molecules.

Blockade of voltage‐gated sodium channels (VGSCs) has been used successfully in the clinic to enable control of pathological firing patterns that occur in conditions as diverse as chronic pain, epilepsy, and arrhythmias. Herein we review the state of the art in marketed sodium channel inhibitors, including a brief compendium of their binding sites and of the cellular and molecular biology of sodium channels. Despite the preferential action of this drug class toward over‐excited cells, which significantly limits potential undesired side effects on other cells, the need to develop a second generation of sodium channel inhibitors to overcome their critical clinical shortcomings is apparent. Current approaches in drug discovery to deliver novel and truly innovative sodium channel inhibitors is next presented by surveying the most recent medicinal chemistry breakthroughs in the field of small molecules and developments in automated patch‐clamp platforms. Various strategies aimed at identifying small molecules that target either particular isoforms of sodium channels involved in specific diseases or anomalous sodium channel currents, irrespective of the isoform by which they have been generated, are critically discussed and revised.

Editorial: Channeling Drug Discovery

Introduction Ion channels are pore-forming proteins in membranes of cells that comprise approximately 1.5 % (~300 genes) of the human genome and have a unique and wide-spread role in numerous fundamental physiological processes. These include electrical signaling in the heart and the central nervous system (CNS), fluid secretion in the lung, gastrointestinal tract and kidney, and hormone secretion. More than 60 different inherited ion channel diseases, known as “channelopathies”, underline the physiological importance of this protein class. Consequently, ion channels provide a major class of drug targets (~10 % of known drugs are modulators of ion channels). Many small-molecule drugs addressing ion channels are currently in clinical use, including classical drugs for the treatment of cardiac diseases, like verapamil and nifedipine, which target L-type calcium channels, and amiodarone and sotalol, targeting potassium channels (hERG). Sodium channel blockers, such as phenytoin and lidocaine are used as anticonvulsants and local anesthetics, respectively, whereas benzodiazepines modulating the g-aminobutyric acid (GABA) channels are used as antidepressants. In contrast to these small molecules, only relatively little advancement has been made in the field of antibody-based drugs against ion channels. There are several interesting concepts in experimental stages, but so far they are mainly used as pharmacological tools.