| Rapid Screening of Voltage-gated Sodium Channel (VGSC) Isoforms using Planar Array Electrophysiology |
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Presentation: 3A03 Session: Target Biology & Screening: Ion ChannelsTim Dale, Jenni Cryan and Derek Trezise, GlaxoSmithKline R&D Presenting Author: Tim Dale, GlaxoSmithKline - UK VGSCs represent attractive targets for novel local anaesthetics, anticonvulsants and analgesics. However, their voltage gating, ionic dependence and extremely rapid kinetics precludes meaningful SAR screening by any currently available method other than electrophysiology. This presentation will describe the construction and use of primary and selectivity SAR assays for different recombinant VGSC isoforms using the IonWorksHT planar array method (Schroeder et al., 2003: J. Biomol. Screen., 8, 50-64). Data from biophysical and pharmacological experiments including protocols for determining use-dependent block will be described, and an overview of throughput and screening performance will be provided. In the final section, the findings from a VGSC screen on a 1564 compound library using the next generation IonWorks Quattro instrument will be presented. Together, the data confirm the suitability of planar array electrophysiology for VGSC screening, and illustrate how enabling this technology can be for studying this family of proteins. |