Ion channels as drug targets: The next GPCRs

Ion channels are well recognized as important therapeutic targets for treating a number of different pathophysiologies. Historically, however, development of drugs targeting this protein class has been diffi cult. Several challenges associated with molecular-based drug discovery include validation of new channel targets and identification of acceptable medicinal chemistry leads. Proof of concept approaches, focusing on combined molecular biological/ pharmacological studies, have been successful. New, functional, high throughput screening (HTS) strategies developed to identify tractable lead structures, which typically are not abundant in small molecule libraries, have also yielded promising results. Automated cell-based HTS assays can be configured for many different types of ion channels using fluorescence methods to monitor either changes in membrane potential or intracellular calcium with high density format plate readers. New automated patch clamp technologies provide secondary screens to confirm the activity of hits at the channel level, to determine selectivity across ion channel superfamilies, and to provide insight into mechanism of action. The same primary and secondary assays effectively support medicinal chemistry lead development. Together, these methodologies, along with classical drug development practices, provide an opportunity to discover and optimize the activity of ion channel drug development candidates. A case study with voltage-gated sodium channels is presented to illustrate these principles. © 2008 Kaczorowski et al.