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Ion Channels as Drug Targets: The Next GPCRs

2008; Rockefeller University Press; Volume: 131; Issue: 5 Linguagem: Inglês

10.1085/jgp.200709946

1540-7748

Gregory J. Kaczorowski, Owen B. McManus, Birgit T. Priest, María L. García,

Nicotinic Acetylcholine Receptors Study

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 identifi cation 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 confi gured for many different types of ion channels using fl uorescence 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 confi rm 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.