INDOMETHACIN IBUPROFEN-LIKE ANTIINFLAMMATORY AGENTS SELECTIVELY POTENTIATE THE GAMMA-AMINOBUTYRIC ACID-ANTAGONISTIC EFFECTS OF SEVERAL NORFLOXACIN-LIKE QUINOLONE ANTIBACTERIAL AGENTS ON [S-35] T-BUTYLBICYCLOPHOSPHOROTHIONATE BINDING

Four piperazinoquinolone antibacterial drugs (norfloxacin, ciprofloxac in, enoxacin, and pipemidic acid), known to be gamma-amino-butyric aci d (GABA) antagonists, fully reversed the inhibitory effect of GABA on [S-35]t-butylbicyclophosphorothionate ([S-35] TBPS) binding to rat bra in membranes in vitro. Twelve indomethacin/ibuprofen-like arylalkanoic acid (AAA) anti-inflammatory drugs alone had no effect on [S-35]TBPS binding, or on its inhibition by GABA, but potentiated the GABA-antago nistic effects of the four quinolones. Felbinac (4-biphenylacetic acid ) was most potent in this respect (EC50 = 110 nm, together with 5 mum norfloxacin), followed by flurbiprofen > anirolac > metiazinic acid > tolmetin = ketoprofen = fenbufen = indomethacin > fenoprofen > ibuprof en = (+)-naproxen = sulindac. Other anti-inflammatory analgesic drugs, including aspirin, diclofenac, diflunisal, meclofenamic acid, mefenam ic acid, nambumetone, phenacetin, piroxicam, and phenylbutazone, faile d to potentiate the GABA-antagonistic effect of norfloxacin. Felbinac (1 muM) increased the GABA-antagonistic potencies of norfloxacin and e noxacin about 26-fold, while increasing those of ciprofloxacin and pip emidic acid 7-fold and 2.3-fold, respectively. Using subsaturating con centrations of the four quinolones, concentration-response curves for felbinac yielded EC50 values ranging from 110 nm with 5 mum norfloxaci n to 1.3 mum with 100 mum pipemidic acid. Three other piperazinoquinol one antibacterial agents (amifloxacin, difloxacin, and fleroxacin) and four nonpiperazinoquinolone antibacterial agents (oxolinic acid, cino xacin, nalidixic acid, and piromidic acid) were much weaker GABA antag onists and were not significantly potentiated by felbinac. All other k nown GABA(A) receptor blockers tested, including R 5135, pitrazepin, b icuculline, SR 95531, strychnine, D-tubocurarine, thebaine, securinine , theophylline, and caffeine, were not potentiated by felbinac. Our re sults suggest that norfloxacin and related piperazinoquinolones, actin g at GABA(A) receptors, may induce a high affinity binding site for in domethacin/ibuprofen-like anti-inflammatory agents (the AAA site) that , when occupied, reciprocally increases the affinities of the quinolon es for GABA(A) receptors. The AAA binding site may be a new site in th e GABA(A) receptor complex.