EVIDENCE THAT A HYBRID MOLECULE OF NORFLOXACIN AND BIPHENYLACETIC ACID IS A POTENT ANTAGONIST AT THE GABA(A) RECEPTOR

The combination of some fluorinated quinolone antimicrobials and certa in non-steroidal antiinflammatory drugs (NSAIDs), such as fenbufen, ha s been reported to elicit serious convulsions in humans. Fluoroquinolo nes, including norfloxacin (NFLX) and NSAIDs synergistically inhibit G ABA(A) receptors. The mechanism(s) of the synergism, however, at prese nt 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 GABA(A) antagon ist, 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 techniqu e. Hybrid-1, with a -CONH(CH2)(3)- chain between NFLX and BPA, inhibit ed the GABA response more potently than co-treatment with NFLX and BPA . In contrast, hybrid-2 with a -CONH- chain between NFLX and BPA, exhi bited only a weak inhibition of the GABA response. The characterizatio n of the inhibition of the GABA response in the presence of hybrid-1 w as similar to that of the combination of NFLX and BPA regarding the fo llowing: (1) there was a rightward parallel shift of the concentration -response curve bf GABA at lower concentrations and a suppression of t he maximal response to GABA at higher concentrations; (2) it was volta ge-independent; and (3) there was no influence on the reversal potenti al of the GABA response. These results therefore suggest that NFLX and BPA interact with the GABA(A) receptor at nearby sites and thus suppr ess the GABA response. Copyright (C) 1996 Elsevier Science Ltd