Ion channels are difficult to study and are considered to be largely unexploited compared with other drug target classes. In principle, there are two methods for exploring ion channels: direct and indirect.
The indirect method involves setting up assays, based on intracellular flurorescent probes, which can signal changes in intracellular ion concentrations or membrane potential. The main benefits of this method are the high throughput and relatively low cost per data point. However, its measurements are less accurate and typically have low sensitivity, making it possible to study only certain types of ion channels. The indirect measurements also require a direct follow-up screen to filter out any false positives. Importantly, any false negatives from the primary indirect screens will never be detected, so entire chemotypes of compounds may be lost through indirect non-functional screening.
Only one technique is available that allows direct recording of the ion fluxes across single ion channels or through entire cell membranes. This technique, known as patch clamping, was developed by Erwin Neher and Bert Sakmann in 1974 and is the first technique to measure the flow of electric current through single-ion channels. In 1991 Neher and Sakmann received the Nobel Prize for this discovery.
Because of the very low throughput of traditional methods, patch clamping was classically left until late in lead selection by drug developers. In some cases, blockbuster drugs have made it to the market, but insufficient ion channel validation has resulted in problems becoming apparant post-launch. For example, Hismanal (astemizole; Janssen), Propulsid (cisapride; Johnson & Johnson) and Serdolect (sertindole; Lundbeck) have all been withdrawn by the FDA owing to unforseen effetcs on the cardiac potassium channel, hERG. The drugs were developed for non-cardiac indications, but had the potential to induce arrhythmia, cardiac arrest and, in some cases, death.
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