Possible intermolecular interaction between quinolones and biphenylacetic acid inhibits gamma-aminobutyric acid receptor sites.
The combination of some new quinolone antibacterial agents with 4-biphenylacetic acid (BPAA), a metabolite of fenbufen, is known to specifically induce functional blockade of the gamma-aminobutyric acid (GABA) receptors. The mechanisms of these drug interactions were further examined. Scatchard analysis of [3H]muscimol binding to rat brain plasma membranes in the presence of enoxacin and BPAA revealed that a significant decrease in the number of muscimol binding sites was produced without affecting the affinity of binding to the receptors. In the presence of norfloxacin, BPAA inhibited muscimol binding the most potently of the six BPAA-related compounds tested. Fenbufen and 9,10-dihydro-gamma-oxo-2-phenanthrenebutyric acid also inhibited the binding, and 4-biphenylcarboxylic acid and methyl 4-biphenylacetate inhibited it slightly, 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 structure) inhibited muscimol binding, and intracisternal injection of this hybrid caused clonic convulsions in mice more potently than the combination of norfloxacin and BPAA did. In contrast, a hybrid linked by -CONH- (stretched structure) showed almost no such inhibitory effect. 1H NMR analysis indicated the presence of intramolecular attraction at the quinoline ring of the hybrid exhibiting the antagonistic activity. These results suggest the possibility that quinolones and BPAA interact with the GABA receptor at nearby sites and that the binding affinity of quinolones to the GABA receptors is largely enhanced by the intermolecular interaction with BPAA.
Akahane
K
K
Exploratory Research Laboratories I, Daiichi Pharmaceutical Co., Tokyo, Japan.
Kimura
Y
Y
Tsutomi
Y
Y
Hayakawa
I
I
D000818:Animals; D001665:Binding Sites; D004347:Drug Interactions; D018756:GABA Antagonists / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D009118:Muscimol / Q000378:metabolism; D009643:Norfloxacin / Q000737:chemistry / Q000494:pharmacology*; D010648:Phenylacetates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018079:Receptors, GABA / Q000737:chemistry / Q000378:metabolism; D012640:Seizures / Q000139:chemically induced
D018756:GABA Antagonists; D010648:Phenylacetates; D018079:Receptors, GABA; D009118:Muscimol; C012776:biphenylylacetic acid; D009643:Norfloxacin