Effects of fluoroquinolones on HERG channels and on pancreatic β-cell ATP-sensitive K+ channels

An inhibition of the cardiac rapid delayed rectifier K+ current (IKr) and of the ATP-sensitive K+ (KATP) 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 IKr, which is encoded by human ether-a-go-go-related gene (HERG), and on the ATP-sensitive K+ (KATP) channel from the clonal insulinoma cell line RINm5F. Sparfloxacin blocked HERG currents half-maximally (IC50 value) at a concentration of 33.2 μM, whereas norfloxacin and lomefloxacin each tested at a concentration of 300 μM 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 N1 and an additional dimethylated piperazine ring (compounds C1 and C2) inhibited HERG currents by 7.3-14.7% at test concentrations of 100 μM. The rank order of potency for the inhibition of KATP currents was C2 > C1, C4, sparfloxacin > C3. In conclusion, the structural requirements for fluoroquinolones to inhibit IKr currents and KATP currents appear to differ. The amino group at position C5 seems to be primarily responsible for the strong HERG current blocking property of sparfloxacin. In contrast, for the block of pancreatic β-cell KATP currents by fluoroquinolones the substituents at positions N1, C7 and C8 all might play a role.