Abstract
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.
Footnotes
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doi:10.1124/jpet.106.101162.
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ABBREVIATIONS: AF, atrial fibrillation; IKur, ultrarapidly activating delayed rectifier potassium current; hKv1.5, human Kv1.5; APD, action potential duration; Ito, transient outward potassium current; IKAch, G-protein regulated, muscarinic-activated potassium current; IKr, rapidly activating delayed rectifier potassium current; IKs, slowly activating delayed rectifier potassium current; DPO, diphenyl phosphine oxide; DPO-1, (2-isopropyl-5-methylcyclohexyl) diphenylphosphine oxide; DPO-2, 2-(diphenylphosphinylmethyl)-4′-fluoro-3,5,3′-trimethylbiphenyl; DPO-3, 1,2-diphenylvinyl diphenylphosphinate; DPO-4, 2-methyl-1-(3-nitrophenyl)-1-propenyl diphenylphosphinate; DPO-5, octyl diphenylphosphinate; TEVC, two-electrode voltage-clamp; CHO, Chinese hamster ovary; HBS, HEPES-buffered saline; TEA, tetraethylammonium; IK1, inward rectifier potassium current; MK-499, N-[1′-(6-cyano-1,2,3,4-tetrahydro-2(R)-naphthalenyl)-3,4-dihydro-4(R)-hydroxyspiro[2H-1-benzopyran-2,4′-piperidin]-6-yl] methanesulfonamide; RMP, resting membrane potential; NIP-141/142, (3R*,4S*)-4-cyclopropylamino-3,4-dihydro-2,2-dimethyl-6-(4-methoxy-phenylacethylamino)-7-nitro-2H-1-benzopyran-3-ol; AVE0118, 2′-{[2-(4-methoxyphenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid (2-pyridin-3-yl-ethyl)-amide; S9947, [2′-(2-pyridin-2-yl-ethylcarbamoyl)-biphenyl-2-ylmethyl]-carbamic acid benzyl ester; S20951, 2′-{[2-(4-methoxy-phenyl)-acetylamino]-methyl}-biphenyl-2-carboxylic acid 2,4-difluorobenzylamide; RSD1235, (1R,2R)-2-[(3R)-hydroxypyrrolidinyl]-1-(3,4-dimethoxy-phenethoxy-cyclohexane; SSR149774C, 2-butyl-3-{4-[3-(dibutylamino)propyl]benzoyl}-1-benzofuran-5-carboxylate isopropyl fumarate.
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↵1 Current affiliation: Department of Preclinical Strategy and Safety Evaluation, Merck Research Laboratories, West Point, PA 19486.
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↵2 Current affiliation: Department of Pain Pharmacology, Merck Research Laboratories, West Point, PA 19486.
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↵3 Current affiliation: Pfizer Global Research and Development, Groton, CT 06340.
- Received January 12, 2006.
- Accepted March 3, 2006.
- The American Society for Pharmacology and Experimental Therapeutics
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