Novel, potent inhibitors of human Kv1.5 K+ channels and ultrarapidly activating delayed rectifier potassium current.
We have identified a series of diphenyl phosphine oxide (DPO) compounds that are potent frequency-dependent inhibitors of cloned human Kv1.5 (hKv1.5) channels. DPO inhibited hKv1.5 expressed in Chinese hamster ovary cells in a concentration-dependent manner preferentially during channel activation and slowed the deactivating tail current, consistent with a predominant open-channel blocking mechanism. Varying kinetics of DPO interaction with Kv1.5 channels resulted in differing potencies and frequency dependencies of inhibition that were comparable for both expressed hKv1.5 current and native ultrarapidly activating delayed rectifier potassium current (IKur) in human atrial myocytes. Selectivity of DPO versus other cardiac K+ channels was demonstrated in human atrial myocytes (IKur versus transient outward potassium current) and guinea pig ventricular myocytes [IKur versus rapidly activating delayed rectifier potassium current (IKr), slowly activating delayed rectifier potassium current (IKs) and inward rectifier potassium current (IK1), and one compound (DPO-1) was shown to be 15-fold more selective for Kv1.5 versus Kv3.1 channels expressed in Xenopus oocytes. DPO-1 also prolonged action potentials of isolated human atrial but not ventricular myocytes, in contrast to the effect of a selective IKr blocker. The selectivity and kinetics of inhibition hKv1.5 and IKur by DPO and the resulting selective prolongation of atrial repolarization could provide an effective profile for treatment of supraventricular arrhythmias.
Lagrutta
Armando
A
Merck Research Laboratories, Cellular Electrophysiology-Preclinical Strategy and Safety Evaluation, West Point, PA 19486, USA.
Wang
Jixin
J
Fermini
Bernard
B
Salata
Joseph J
JJ
D000200:Action Potentials / Q000187:drug effects*; D000818:Animals; D001713:Biphenyl Compounds / Q000737:chemistry / Q000494:pharmacology*; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D006168:Guinea Pigs; D006801:Humans; D051666:Kv1.5 Potassium Channel / Q000037:antagonists & inhibitors*; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009865:Oocytes / Q000187:drug effects* / Q000378:metabolism; D009943:Organophosphorus Compounds / Q000737:chemistry / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000737:chemistry / Q000494:pharmacology*; D014162:Transfection; D014982:Xenopus laevis
D001713:Biphenyl Compounds; D051666:Kv1.5 Potassium Channel; D009943:Organophosphorus Compounds; D026902:Potassium Channel Blockers