The 5-HT(4) agonists cisapride, mosapride, and CJ-033466, a Novel potent compound, exhibit different human ether-a-go-go-related gene (hERG)-blocking activities.
The blocking effect of three 5-HT(4) agonists, cisapride, mosapride, and the newly discovered CJ-033466 on the human ether-a-go-go-related gene (hERG) channel was studied using a whole cell patch-clamp technique in HEK293 cells. Cisapride was found to be the most potent of the hERG blockers. CJ-033466 had the widest safety margin between its hERG blocking activity and 5-HT(4) agonism among the tested compounds. This suggests a lower clinical risk of cardiac arrhythmia in CJ-033466 compared with the other 2 agonists. Therefore, CJ-033466 has the potential to be a drug with higher therapeutic efficacy and less cardiac risk than both cisapride and mosapride.
Toga
Tetsuo
T
Nagoya Laboratories, Pfizer Global Research and Development, Pfizer Japan Inc., Taketoyo, Aichi, Japan. toga@japan-net.ne.jp
Kohmura
Yumi
Y
Kawatsu
Ryoichi
R
D000631:Aminopyridines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001145:Arrhythmias, Cardiac / Q000139:chemically induced; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002460:Cell Line; D020117:Cisapride / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009025:Morpholines / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*
D000631:Aminopyridines; D001549:Benzamides; C525058:CJ 033466; D051638:Ether-A-Go-Go Potassium Channels; D007093:Imidazoles; D009025:Morpholines; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists; C062720:mosapride; D020117:Cisapride