title: Effects of fluoroquinolones on HERG channels and on pancreatic beta-cell ATP-sensitive K+ channels.
abstract: An inhibition of the cardiac rapid delayed rectifier K(+) current (I(Kr)) and of the ATP-sensitive K(+) (K(ATP)) current seems to be involved in the mechanisms of the cardiotoxic effects and the alterations in glucose homeostasis, respectively, induced by some fluoroquinolones. The aim of the present study was to compare the effects of fluoroquinolone derivatives on the pore-forming subunit of the cardiac I(Kr), which is encoded by human ether-a-go-go-related gene (HERG), and on the ATP-sensitive K(+) (K(ATP)) channel from the clonal insulinoma cell line RINm5F. Sparfloxacin blocked HERG currents half-maximally (IC(50) value) at a concentration of 33.2 microM, whereas norfloxacin and lomefloxacin each tested at a concentration of 300 microM inhibited HERG currents only by 2.8+/-3.6% and 12.3+/-4.7%, respectively. Four newly synthesized fluoroquinolone derivatives with either a p-fluoro-phenyl (compound C3) or an o-fluoro-phenyl (compound C4) substituent at position N(1) and an additional dimethylated piperazine ring (compounds C1 and C2) inhibited HERG currents by 7.3-14.7% at test concentrations of 100 microM. The rank order of potency for the inhibition of K(ATP) currents was C2>C1, C4, sparfloxacin>C3. In conclusion, the structural requirements for fluoroquinolones to inhibit I(Kr) currents and K(ATP) currents appear to differ. The amino group at position C(5) seems to be primarily responsible for the strong HERG current blocking property of sparfloxacin. In contrast, for the block of pancreatic beta-cell K(ATP) currents by fluoroquinolones the substituents at positions N(1), C(7) and C(8) all might play a role.
authors.affiliation: Federal Institute for Drugs and Medical Devices, Kurt-Georg-Kiesinger-Allee 3, D-53175 Bonn, Germany. j.zuenkler@bfarm.de <j.zuenkler@bfarm.de>
authors.forename: Bernd J
authors.initials: BJ
authors.lastname: Zünkler
authors.forename: Sonja
authors.initials: S
authors.lastname: Claassen
authors.forename: Maria
authors.initials: M
authors.lastname: Wos-Maganga
authors.forename: Ingo
authors.initials: I
authors.lastname: Rustenbeck
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
mesh_terms: D000465:Algorithms; D000818:Animals; D003627:Data Interpretation, Statistical; D000072237:ERG1 Potassium Channel; D004594:Electrophysiology; D051638:Ether-A-Go-Go Potassium Channels / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D024841:Fluoroquinolones / Q000494:pharmacology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism*; D054086:KATP Channels; D018408:Patch-Clamp Techniques; D010879:Piperazines / Q000737:chemistry / Q000494:pharmacology; D024661:Potassium Channels, Inwardly Rectifying / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C489478:BIK channel; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D024841:Fluoroquinolones; D054086:KATP Channels; C000606913:KCNH2 protein, human; D010879:Piperazines; D024661:Potassium Channels, Inwardly Rectifying; C092520:uK-ATP-1 potassium channel