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Journal of Biomolecular Screening
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Identifying Modulators of hERG Channel Activity Using the PatchXpress® Planar Patch Clamp

Adrienne E. Dubin

Pain & Related Disorders, Johnson & Johnson Pharmaceutical Research & Development, San Diego, CA

Nadia Nasser

Pain & Related Disorders, Johnson & Johnson Pharmaceutical Research & Development, San Diego, CA

Jutta Rohrbacher

Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

An N. Hermans

Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

Roger Marrannes

CNS Pain & Alzheimer, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

Christopher Grantham

Psychiatry I, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

Koen Van Rossem

Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium, Barrier Therapeutics NV, Geel, Belgium

Miroslav Cik

Assay Development & High Throughput Screening, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

Sandra R. Chaplan

Pain & Related Disorders, Johnson & Johnson Pharmaceutical Research & Development, San Diego, CA

David Gallacher

Center of Excellence for Cardiovascular Safety Research, Johnson & Johnson Pharmaceutical Research & Development, a division of Janssen Pharmaceutica NV, Beerse, Belgium

Jia Xu

AVIVA Biosciences Corp., San Diego, CA

Antonio Guia

AVIVA Biosciences Corp., San Diego, CA

Nicholas G. Byrne

Molecular Devices Corp., Union City, CA

Chris Mathes

Molecular Devices Corp., Union City, CA, Sophion Bioscience, Inc., Annandale, NJ

The authors used the PatchXpress® 7000A system to measure compound activity at the hERG channel using procedures that mimicked the "gold-standard" conventional whole-cell patch clamp. A set of 70 compounds, including hERG antagonists with potencies spanning 3 orders of magnitude, were tested on hERG302-HEK cells using protocols aimed at either identifying compound activity at a single concentration or obtaining compound potency from a cumulative concentration dependence paradigm. After exposure to compounds and subsequent washout of the wells to determine reversibility of the block, blockade by a reference compound served as a quality control. Electrical parameters and voltage dependence were similar to those obtained using a conventional whole-cell patch clamp. Rank order of compound potency was also comparable to that determined by conventional methods. One exception was flunarizine, a particularly lipophilic compound. The PatchXpress® accurately identified the activity of 29 moderately potent antagonists, which only weakly displace radiolabeled astemizole and are false negatives in the binding assay. Finally, no false hits were observed from a collection of relatively inactive compounds. High-quality data acquisition by PatchXpress® should help accelerate secondary screening for ion channel modulators and the drug discovery process

Key Words: voltage clamp • automation • throughput • assay • human ether-a-go-go related gene potassium channel

Journal of Biomolecular Screening, Vol. 10, No. 2, 168-181 (2005)
DOI: 10.1177/1087057104272295
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