Inhibition of GABAA Receptor Chloride Channel by Quinolones and Norfloxacin-Biphenylacetic Acid Hybrid Compounds

Abstract

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 μM and above. In combination with 10 μM 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 μM) 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-30 μM) inhibited muscimol-stimulated 36Cl− uptake more potently than did the combination of NFLX (10 nM-100 μM) and 10 μM BPAA. In contrast, another hybrid linked by -CONH- (stretched structure) exhibited a weak inhibitory effect at 10 μM. 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. Copyright © 1996 Elsevier Science Ltd