Evidence that a hybrid molecule of norfloxacin and biphenylacetic acid is a potent antagonist at the GABAA receptor.

The combination of some fluorinated quinolone antimicrobials and certain non-steroidal anti-inflammatory drugs (NSAIDs), such as fenbufen, has been reported to elicit serious convulsions in humans. Fluoroquinolones, including norfloxacin (NFLX) and NSAIDs synergistically inhibit GABAA receptors. The mechanism(s) of the synergism, however, at present remains unclear. In the present study, the hypothesis that NFLX and biphenylacetic acid (BPA), an active metabolite of fenbufen, undergo an intermolecular interaction to produce a more potent GABAA antagonist, was investigated by examining the effects of two hybrid molecules of NFLX linked with BPA on GABA-evoked whole cell currents, recorded from rat hippocampal neurons using the perforated-patch clamp technique. Hybrid-1, with a -CONH(CH2)3- chain between NFLX and BPA, inhibited the GABA response more potently than co-treatment with NFLX and BPA. In contrast, hybrid-2 with a -CONH- chain between NFLX and BPA, exhibited only a weak inhibition of the GABA response. The characterization of the inhibition of the GABA response in the presence of hybrid-1 was similar to that of the combination of NFLX and BPA regarding the following: (1) there was a rightward parallel shift of the concentration-response curve of GABA at lower concentrations and a suppression of the maximal response to GABA at higher concentrations; (2) it was voltage-independent; and (3) there was no influence on the reversal potential of the GABA response. These results therefore suggest that NFLX and BPA interact with the GABAA receptor at nearby sites and thus suppress the GABA response.