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This version was published on September 1, 2006
Journal of Biomolecular Screening, Vol. 11, No. 6, 672-677 (2006)
DOI: 10.1177/1087057106289210

High-Throughput Screening for N-Type Calcium Channel Blockers Using a Scintillation Proximity Assay

Sui-Po Zhang

Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, Pennsylvania

Jack Kauffman

Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, Pennsylvania

Susan K. Yagel

Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, Pennsylvania

Ellen E. Codd

Drug Discovery, Johnson & Johnson Pharmaceutical Research and Development, LLC, Spring House, Pennsylvania

N-type calcium channels located on presynaptic nerve terminals regulate neurotransmitter release, including that from the spinal terminations of primary afferent nociceptors. Accordingly, N-type calcium channel blockers may have clinical utility as analgesic drugs. A selective N-type calcium channel inhibitor, ziconotide (Prialt), is a neuroactive peptide recently marketed as a novel nonopioid treatment for severe chronic pain. To develop a small-molecule N-type calcium channel blocker, the authors developed a 96-well plate high-throughput screening scintillation proximity assay (SPA) for N-type calcium channel blockers using [125I]-labeled {omega}-conotoxin GVIA as a channel-specific ligand. Assay reagents were handled using Caliper’s Allegro automation system, and bound ligands were detected using a PerkinElmer TopCount. Using this assay, more than 150,000 compounds were screened at 10 µM and approximately 340 compounds were identified as hits, exhibiting at least 40% inhibition of [125I]GVIA binding. This is the 1st demonstration of the use of [125I]-labeled peptides with SPA beads to provide a binding assay for the evaluation of ligand binding to calcium channels. This assay could be a useful tool for drug discovery.

Key Words: calcium channel • SPA • {omega}-conotoxin GVIA • HTS


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