Inhibition of GABAA receptor chloride channel by quinolones and norfloxacin-biphenylacetic acid hybrid compounds.
Receptor binding studies have shown that the combination of some new quinolone antibacterial agents with 4-biphenylacetic acid (BPAA), a metabolite of fenbufen, inhibits GABAA receptors. In order to elucidate further the mechanism of these drug interactions, the effect of quinolone antibacterial agents on muscimol-stimulated 36Cl- uptake in rat cerebral cortical synaptoneurosomes was investigated in the absence or presence of BPAA. In the absence of BPAA, quinolones such as norfloxacin (NFLX) and enoxacin attenuated muscimol-stimulated 36Cl- uptake at 10 microM and above. In combination with 10 microM BPAA, the inhibitory effect of these drugs was potentiated and there was a parallel shift of the inhibition curves to the left for these drugs. BPAA alone (1 and 10 microM) did not affect basal or muscimol-stimulated 36Cl- uptake. Hybrid molecules of NFLX and BPAA were synthesized and their inhibitory potency was also investigated. Inhibition curves of muscimol-stimulated 36Cl- uptake revealed that a hybrid with a -CONH(CH2)3- chain between NFLX and BPAA (flexible structure) (1 nM-20 microM) inhibited muscimol-stimulated 36Cl- uptake more potently than did the combination of NFLX (10 nm-100 microM) and 10 microM BPAA. In contrast, another hybrid linked by -CONH-(stretched structure) exhibited a weak inhibitory effect at 10 microM. These results suggest that quinolones in combination with BPAA bind to GABAA receptors, thus inhibiting Cl- channel activity, and that the inhibitory potency of quinolones may be enhanced by an intermolecular interaction with BPAA.
Ito
Y
Y
Department of Pharmacology, College of Pharmacy, Nihon University, Chiba, Japan.
Miyasaka
T
T
Fukuda
H
H
Akahane
K
K
Kimura
Y
Y
D000818:Animals; D000890:Anti-Infective Agents / Q000494:pharmacology*; D018118:Chloride Channels / Q000187:drug effects / Q000378:metabolism*; D002713:Chlorine / Q000378:metabolism; D015365:Enoxacin / Q000494:pharmacology; D018755:GABA Agonists / Q000494:pharmacology; D018756:GABA Antagonists / Q000494:pharmacology; D058787:GABA-A Receptor Antagonists; D008297:Male; D009118:Muscimol / Q000494:pharmacology; D009643:Norfloxacin / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology; D015363:Quinolones / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
D000890:Anti-Infective Agents; D018118:Chloride Channels; D018755:GABA Agonists; D018756:GABA Antagonists; D058787:GABA-A Receptor Antagonists; D010648:Phenylacetates; D011724:Pyridazines; D015363:Quinolones; D009118:Muscimol; D015365:Enoxacin; D002713:Chlorine; C049853:gabazine; D009643:Norfloxacin