POSSIBLE INTERMOLECULAR INTERACTION BETWEEN QUINOLONES AND BIPHENYLACETIC ACID INHIBITS GAMMA-AMINOBUTYRIC-ACID RECEPTOR-SITES

The combination of some new quinolone antibacterial agents with 4-biph enylacetic acid (BPAA), a metabolite of fenbufen, is known to specific ally induce functional blockade of the gamma-aminobutyric acid (GABA) receptors. The mechanisms of these drug interactions were further exam ined. Scatchard analysis of [H-3] muscimol binding to rat brain plasma membranes in the presence of enoxacin and BPAA revealed that a signif icant decrease in the number of muscimol binding sites was produced wi thout affecting the affinity of binding to the receptors. In the prese nce of norfloxacin, BPAA inhibited muscimol binding the most potently of the six BPAA-related compounds tested. Fenbufen and 9,10-dihydro-ga mma-oxo-2-phenanthrenebutyric acid also inhibited the binding, and 4 b iphenylcarboxylic acid and methyl 4-biphenylacetate inhibited it sligh tly, but 3-benzoylpropionic acid exhibited no competitive inhibition. Accordingly, hybrid molecules of norfloxacin and BPAA were synthesized for stereochemical analysis of these drug interactions. A hybrid with a -CONH(CH2)(3)- chain between norfloxacin and BPAA (flexible structu re) inhibited muscimol binding, and intracisternal injection of this h ybrid caused clonic convulsions in mice more potently than the combina tion of norfloxacin and BPAA did. In contrast, a hybrid linked by -CON H-(stretched structure) showed almost no such inhibitory effect. H-1 N MR analysis indicated the presence of intramolecular attraction at the quinoline ring of the hybrid exhibiting the antagonistic activity. Th ese results suggest the possibility that quinolones and BPAA interact with the GABA receptor at nearby sites and that the binding affinity o f quinolones to the GABA receptors is largely enhanced by the intermol ecular interaction with BPAA.