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Identifying modulators of hERG channel activity using the PatchXpress planar patch clamp.
Adrienne E Dubin1, Nadia Nasser, Jutta Rohrbacher
1Pain and Related Disorders, Johnson and Johnson Pharmaceutical Research and Development, San Diego, CA 92121, USA. adubin@prdus.jnj.com
Journal of Biomolecular Screening
|April 1, 2005
Summary
The PatchXpress system effectively measures compound activity at the hERG channel, offering a faster alternative to traditional methods. It accurately identifies drug candidates, accelerating ion channel modulator discovery.
Area of Science:
- Pharmacology
- Electrophysiology
- Drug Discovery
Background:
- The hERG channel is a critical target for drug safety assessment due to its role in cardiac repolarization.
- Conventional whole-cell patch clamp is the gold standard for measuring hERG channel activity but is time-consuming and labor-intensive.
- There is a need for high-throughput, reliable methods to screen compounds for hERG channel activity.
Purpose of the Study:
- To evaluate the performance of the PatchXpress 7000A system for measuring compound activity at the hERG channel.
- To compare the PatchXpress system's results with conventional whole-cell patch clamp methods.
- To assess the utility of the PatchXpress system in accelerating drug discovery for ion channel modulators.
Main Methods:
- Utilized the PatchXpress 7000A system to perform electrophysiological measurements on hERG302-HEK cells.
- Tested a set of 70 compounds, including hERG antagonists with varying potencies.
- Employed protocols for single-concentration activity identification and cumulative concentration-dependent potency determination.
- Included compound washout steps to assess reversibility and used a reference compound for quality control.
Main Results:
- Electrical parameters and voltage dependence obtained with PatchXpress were comparable to conventional patch clamp.
- The rank order of compound potency determined by PatchXpress correlated well with conventional methods, with one exception (flunarizine).
- PatchXpress successfully identified 29 moderately potent antagonists missed by binding assays, demonstrating improved sensitivity.
- No false positive hits were observed from inactive compounds.
Conclusions:
- The PatchXpress 7000A system provides high-quality data for hERG channel compound activity assessment.
- The system mimics conventional patch clamp performance, offering a more efficient alternative.
- PatchXpress has the potential to significantly accelerate secondary screening and the overall drug discovery process for ion channel modulators.