The action of the novel gastrointestinal prokinetic prucalopride on the HERG K+ channel and the common T897 polymorph.
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.
Chapman
Hugh
H
Institute of Biotechnology, University of Helsinki, Helsinki, Finland. hugh.chapman@orionpharma.com
Pasternack
Michael
M
D001572:Benzofurans / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D005838:Genotype; D006801:Humans; D007700:Kinetics; D008564:Membrane Potentials / Q000187:drug effects; D018408:Patch-Clamp Techniques; D020641:Polymorphism, Single Nucleotide; D013997:Time Factors; D014162:Transfection
D001572:Benzofurans; D051638:Ether-A-Go-Go Potassium Channels; C406662:prucalopride