Predicting changes in cardiac myocyte contractility during early drug discovery with in vitro assays
| Autor: | Duncan Armstrong, J.-P. Valentin, N. Abi Gerges, Joanne Bowes, Chris Pollard, Matthew Bridgland-Taylor, Michael J. Morton |
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| Rok vydání: | 2014 |
| Předmět: |
Inotrope
Cardiac function curve Patch-Clamp Techniques Calcium Channels L-Type CHO Cells Pharmacology Biology Ligands Transfection Toxicology Risk Assessment Membrane Potentials Contractility Automation Radioligand Assay Cricetulus Dogs Predictive Value of Tests Cricetinae Drug Discovery Toxicity Tests Animals Humans Myocyte Myocytes Cardiac L-type calcium channel Binding Sites Calcium channel Cardiac myocyte Myocardial Contraction High-Throughput Screening Assays Phenylalkylamine binding Female Protein Binding |
| Zdroj: | Toxicology and Applied Pharmacology. 279:87-94 |
| ISSN: | 0041-008X |
| DOI: | 10.1016/j.taap.2014.06.005 |
| Popis: | Cardiovascular-related adverse drug effects are a major concern for the pharmaceutical industry. Activity of an investigational drug at the L-type calcium channel could manifest in a number of ways, including changes in cardiac contractility. The aim of this study was to define which of the two assay technologies – radioligand-binding or automated electrophysiology – was most predictive of contractility effects in an in vitro myocyte contractility assay. The activity of reference and proprietary compounds at the L-type calcium channel was measured by radioligand-binding assays, conventional patch-clamp, automated electrophysiology, and by measurement of contractility in canine isolated cardiac myocytes. Activity in the radioligand-binding assay at the L-type Ca channel phenylalkylamine binding site was most predictive of an inotropic effect in the canine cardiac myocyte assay. The sensitivity was 73%, specificity 83% and predictivity 78%. The radioligand-binding assay may be run at a single test concentration and potency estimated. The least predictive assay was automated electrophysiology which showed a significant bias when compared with other assay formats. Given the importance of the L-type calcium channel, not just in cardiac function, but also in other organ systems, a screening strategy emerges whereby single concentration ligand-binding can be performed early in the discovery process with sufficient predictivity, throughput and turnaround time to influence chemical design and address a significant safety-related liability, at relatively low cost. |
| Databáze: | OpenAIRE |
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