title: Block of hERG channel by ziprasidone: biophysical properties and molecular determinants.
abstract: Ziprasidone, an antipsychotic agent, delays cardiac repolarization and, thus, prolongs the QT interval of the cardiac ECG. In this study, we examined the biophysical properties and the molecular determinants of the ziprasidone block of wild-type hERG potassium channels stably expressed in HEK-293 cells or wild-type and mutant hERG channels expressed in Xenopus oocytes. In stably transfected HEK-293 cells, ziprasidone blocked wild-type hERG current in a voltage- and concentration-dependent manner (IC(50)=120nM, 0mV, 37 degrees C). Ziprasidone showed minimal tonic block of hERG current estimated during a depolarizing voltage (-20 or +30mV) or evaluated by the envelope of tails test (+30mV). Rate of the block onset was rapid, but not significantly affected by test potentials ranging from -20 to +30mV (time constant (tau)=114+/-14ms at +30mV). The time constant of the slow component of hERG current deactivation (at -50mV) was significantly increased by ziprasidone (tau=1776+/-90 versus 1008+/-71ms, P<0.01). Time course of channel inactivation was slowed by ziprasidone in a voltage-dependent manner. The V(1/2) values for steady-state activation and inactivation of hERG channel in HEK-293 cells were not significantly altered by ziprasidone. In Xenopus oocytes, ziprasidone exhibited less potent block of wild-type hERG current (IC(50)=2.8microM, 0mV, 23 degrees C). Mutation of the aromatic residues (Tyr-652 or Phe-656) located in the S6 domain of hERG dramatically reduced the potency of channel block by ziprasidone (IC(50)>0.4 and 1mM at 0mV for Y652A and F656A, respectively). In conclusion, ziprasidone preferentially binds to and blocks open hERG channels. Tyr-652 and Phe-656 are two critical residues in the ziprasidone-binding site.
authors.affiliation: Department of Integrative Pharmacology, Abbott Laboratories, 100 Abbott Park Road, Abbott Park, IL 60064, USA. zhi.su@abbott.com
authors.forename: Zhi
authors.initials: Z
authors.lastname: Su
authors.forename: Jun
authors.initials: J
authors.lastname: Chen
authors.forename: Ruth L
authors.initials: RL
authors.lastname: Martin
authors.forename: Jeffrey S
authors.initials: JS
authors.lastname: McDermott
authors.forename: Bryan F
authors.initials: BF
authors.lastname: Cox
authors.forename: Murali
authors.initials: M
authors.lastname: Gopalakrishnan
authors.forename: Gary A
authors.initials: GA
authors.lastname: Gintant
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D002460:Cell Line; D003001:Cloning, Molecular; D004305:Dose-Response Relationship, Drug; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D009154:Mutation; D009865:Oocytes / Q000187:drug effects / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*; D014981:Xenopus
chemical_list: D014150:Antipsychotic Agents; D051638:Ether-A-Go-Go Potassium Channels; D010879:Piperazines; D026902:Potassium Channel Blockers; D013844:Thiazoles; C092292:ziprasidone