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The action of the novel gastrointestinal prokinetic prucalopride on the HERG K+ channel and the common T897 polymorph.
Eur J Pharmacol. 2007 Jan 12; 554(2-3):98-105.EJ

Abstract

The human ether-à-go-go related gene (HERG) encodes the alpha-subunit of a delayed rectifier potassium channel important in the repolarisation of the cardiac action potential. Excessive action potential prolongation through HERG channel inhibition is associated with a risk of torsade de pointes arrhythmias and is a major challenge for drug development. The acute effects of the novel prokinetic prucalopride were examined on heterologously expressed HERG channels in human embryonic kidney (HEK) 293 cells using the whole-cell patch-clamp technique. Prucalopride inhibited HERG channels in a concentration-dependent manner with an IC(50) of 4.1 microM. Prucalopride significantly slowed channel deactivation and recovery from inactivation, accelerated and altered the extent of inactivation. Similar concentration-dependency and kinetic changes were observed with the minor T897 polymorphic HERG variant. Prucalopride block was frequency-independent due to rapid state-dependent block, with binding occurring in the open and inactivated states. Though prucalopride blocks HERG channels this is unlikely to be significant at clinically relevant concentrations.

Authors+Show Affiliations

Institute of Biotechnology, University of Helsinki, Helsinki, Finland. hugh.chapman@orionpharma.comNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

17109852

Citation

Chapman, Hugh, and Michael Pasternack. "The Action of the Novel Gastrointestinal Prokinetic Prucalopride On the HERG K+ Channel and the Common T897 Polymorph." European Journal of Pharmacology, vol. 554, no. 2-3, 2007, pp. 98-105.
Chapman H, Pasternack M. The action of the novel gastrointestinal prokinetic prucalopride on the HERG K+ channel and the common T897 polymorph. Eur J Pharmacol. 2007;554(2-3):98-105.
Chapman, H., & Pasternack, M. (2007). The action of the novel gastrointestinal prokinetic prucalopride on the HERG K+ channel and the common T897 polymorph. European Journal of Pharmacology, 554(2-3), 98-105.
Chapman H, Pasternack M. The Action of the Novel Gastrointestinal Prokinetic Prucalopride On the HERG K+ Channel and the Common T897 Polymorph. Eur J Pharmacol. 2007 Jan 12;554(2-3):98-105. PubMed PMID: 17109852.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The action of the novel gastrointestinal prokinetic prucalopride on the HERG K+ channel and the common T897 polymorph. AU - Chapman,Hugh, AU - Pasternack,Michael, Y1 - 2006/10/18/ PY - 2006/06/28/received PY - 2006/10/03/revised PY - 2006/10/06/accepted PY - 2006/11/18/pubmed PY - 2007/3/7/medline PY - 2006/11/18/entrez SP - 98 EP - 105 JF - European journal of pharmacology JO - Eur. J. Pharmacol. VL - 554 IS - 2-3 N2 - The human ether-à-go-go related gene (HERG) encodes the alpha-subunit of a delayed rectifier potassium channel important in the repolarisation of the cardiac action potential. Excessive action potential prolongation through HERG channel inhibition is associated with a risk of torsade de pointes arrhythmias and is a major challenge for drug development. The acute effects of the novel prokinetic prucalopride were examined on heterologously expressed HERG channels in human embryonic kidney (HEK) 293 cells using the whole-cell patch-clamp technique. Prucalopride inhibited HERG channels in a concentration-dependent manner with an IC(50) of 4.1 microM. Prucalopride significantly slowed channel deactivation and recovery from inactivation, accelerated and altered the extent of inactivation. Similar concentration-dependency and kinetic changes were observed with the minor T897 polymorphic HERG variant. Prucalopride block was frequency-independent due to rapid state-dependent block, with binding occurring in the open and inactivated states. Though prucalopride blocks HERG channels this is unlikely to be significant at clinically relevant concentrations. SN - 0014-2999 UR - https://www.unboundmedicine.com/medline/citation/17109852/The_action_of_the_novel_gastrointestinal_prokinetic_prucalopride_on_the_HERG_K+_channel_and_the_common_T897_polymorph_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(06)01145-9 DB - PRIME DP - Unbound Medicine ER -