Abstract

Population Patch Clamp™ (PPC) technology was recently introduced byMolecular Devices in the IonWorks™ Quattro system. PPC records from up to 64 cells at a time, and greatly reduces biological variability, achieving nearly 100% success rates and highly consistent data quality (Z’-Factors between 0.6 – 0.8). We conducted a feasibility study for using the IonWorks Quattro system in a primary screen of a focused library (1564 compounds) for modulators of the cardiac sodium channel Nav1.5 (hH1) –an important target for anti-arrhythmia therapeutics.

The screen was carried out in duplicate at a single concentration (10 uM) in less than two working days. There were 37 actives with 50% or more inhibition identified (2.4% hit rate), which were all followed-up for potency (10-point dose-response run in duplicate) and selectivity (counter screened against Kv1.3). A number of compounds show use dependence and selectivity.

This rapid assay campaign demonstrates that the IonWorks Quattro system can be used for directed primary screens of voltage-gated ion channel modulators. The daily throughput of the IonWorks Quattro is >2000 data points per day. It is estimated that a 10,000 compound single-point screen with follow-up pharmacology could be completed in approximately 2-4 working weeks.