Discovery of novel sodium channel inhibitors-A gene family-based approach

Voltage-gated sodium (Na(V)) channel inhibitors are an important class of drugs that are used to treat a number of CNS indications including pain, local anaesthesia, epilepsy and bipolar disorder. These drugs all have their origins in traditional "empirical" pharmacology, and it was only some time after discovery that they were found to inhibit Na(V) channels. The basis for therapeutic selectivity of these drugs within different disease indications is currently unknown. However, the subsequent discovery of a multi-gene family of Na(V) channels suggests a possible mechanism and has opened the way for more targeted approaches to finding improved therapeutic inhibitors. This article describes some ongoing approaches to systematically clone, express and characterise the entire family of Na(V) subtypes in order to better understand their properties and define their individual physiological and pathophysiological roles. As well as providing specific disease validation for individual subtypes, this also provides a panel of reagents for comprehensively exploring the efficacy, selectivity and potency relationships of existing Na(V)-blocking drugs. In this way, a gene family-based approach to Na(V) channels has enabled a "drug-to-target" approach, reversing the more usual "gene-to-target-to-drug" paradigm. Together with recent advances in assay technology, gene family-based approaches are increasing the tractability of these targets and are re-invigorating Na(V) drug discovery within the pharmaceutical industry.