Novel, potent inhibitors of human Kv1.5 K+ channels and ultrarapidly activating delayed rectifier potassium current

The Journal of Pharmacology and Experimental Therapeutics
Armando LagruttaJoseph J Salata

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 ...Continue Reading

References

Mar 1, 1991·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·M M TamkunD M Glover
May 1, 1991·Proceedings of the National Academy of Sciences of the United States of America·C J LuneauR Swanson
Aug 1, 1981·Pflügers Archiv : European journal of physiology·O P HamillF J Sigworth
Jul 11, 1998·Molecular Pharmacology·J J SalataM C Sanguinetti
Nov 3, 2001·Naunyn-Schmiedeberg's Archives of Pharmacology·A BachmannH Gögelein
Dec 18, 2001·Journal of Cardiovascular Pharmacology·Akiko SekiHiroshi Kasanuki
Jan 24, 2002·The Journal of Pharmacology and Experimental Therapeutics·David GodreauStéphane N Hatem
Jan 24, 2002·Nature·Stanley Nattel
Jan 23, 2003·The Journal of Pharmacology and Experimental Therapeutics·Ignacio MorenoEva Delpón
Sep 23, 2003·Circulation Research·David FedidaDavid R Van Wagoner
Apr 23, 2004·Expert Opinion on Investigational Drugs·Sheila A Doggrell, Jules C Hancox
Jun 24, 2004·Expert Opinion on Investigational Drugs·Anirban Choudhury, Gregory Y H Lip
Aug 26, 2004·Current Medicinal Chemistry. Cardiovascular and Hematological Agents·Joachim Brendel, Stefan Peukert
Apr 20, 2005·Journal of Cardiovascular Pharmacology·Kaname SaidaSatoshi Takizawa
Apr 27, 2005·Heart Rhythm : the Official Journal of the Heart Rhythm Society·A John Camm, Irina Savelieva
Jun 7, 2005·Expert Opinion on Emerging Drugs·Redi PeciniChristian Torp-Pedersen
Nov 24, 2005·Journal of Cardiovascular Electrophysiology·David FedidaGregory N Beatch

❮ Previous
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Citations

Dec 2, 2009·Nature Reviews. Drug Discovery·Heike WulffLuis A Pardo
Dec 17, 2010·Assay and Drug Development Technologies·R Kyle PalmerRobert Bryant
Dec 17, 2010·Cardiovascular Research·Ursula Ravens, Erich Wettwer
Apr 23, 2008·Journal of Cardiovascular Pharmacology·Joachim R EhrlichHeinz Gögelein
Jul 28, 2009·American Journal of Physiology. Heart and Circulatory Physiology·Mary M MaleckarNatalia A Trayanova
Dec 12, 2012·Cellular Physiology and Biochemistry : International Journal of Experimental Cellular Physiology, Biochemistry, and Pharmacology·Sobuj MiaFlorian Lang
Feb 16, 2010·Nihon yakurigaku zasshi. Folia pharmacologica Japonica·Toru Yamashita
Nov 28, 2012·PloS One·Wen-Liang ChenYong-Yuan Guan
May 28, 2010·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Karina Alviña, Kamran Khodakhah
Aug 24, 2010·Expert Opinion on Therapeutic Patents·Neil A Castle
Apr 2, 2009·Expert Opinion on Investigational Drugs·Juan TamargoEva Delpón
Aug 3, 2010·Toxicology·Zara HannounDavid C Hay
Oct 28, 2009·Journal of Molecular and Cellular Cardiology·Todd E HaimJeanne M Nerbonne
Jun 13, 2009·Journal of Electrocardiology·Bramah Singh
Oct 29, 2008·Biochemical Pharmacology·Jerzy KarczewskiRobert H Spencer
Sep 9, 2008·Heart Rhythm : the Official Journal of the Heart Rhythm Society·Alexander Burashnikov, Charles Antzelevitch
Sep 18, 2007·Biochemical and Biophysical Research Communications·Evgenia KoutsoukiFlorian Lang
Jun 5, 2016·Cardiac Electrophysiology Clinics·Wei Wu, Michael C Sanguinetti
Nov 4, 2010·Biophysical Journal·Joachim AlmquistMats Jirstrand
Mar 27, 2015·Microcirculation : the Official Journal of the Microcirculatory Society, Inc·Ibra S FancherGregory M Dick
Feb 27, 2010·Journal of Molecular and Cellular Cardiology·Yi-mei DuYu-hua Liao
Feb 26, 2008·Journal of the American College of Cardiology·Joachim R EhrlichStanley Nattel
Sep 13, 2011·Journal of Molecular and Cellular Cardiology·Hui-Jun WuGui-Rong Li
Sep 13, 2012·ACS Medicinal Chemistry Letters·Jonas Boström
Mar 11, 2017·The Korean Journal of Physiology & Pharmacology : Official Journal of the Korean Physiological Society and the Korean Society of Pharmacology·Sung Eun ShinWon Sun Park
Nov 12, 2009·International Journal of Toxicology·Janet S KerrPaul A Andrews
Sep 28, 2017·Journal of Cardiovascular Pharmacology and Therapeutics·Kamalan JeevaratnamA John Camm
May 3, 2018·The Journal of Physiology·Gema Mondejar-ParreñoFrancisco Perez-Vizcaino
Mar 27, 2018·Journal of the American Heart Association·Johannes SchmidRudolf Schubert
Apr 3, 2014·Physiological Reviews·Nicole SchmittSøren-Peter Olesen
May 16, 2015·Journal of Cardiovascular Pharmacology·Said El-HaouJames T Milnes

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