Study on mechanism of convulsant activity of pyridon-carboxylic acid derivatives

由于有报道称新喹诺酮类药物可诱导惊厥，我们使用小鼠突触膜研究了新喹诺酮类药物对哺乳动物中枢神经系统中抑制性递质γ-氨基丁酸（GABA）受体结合的影响。新喹诺酮类药物以浓度依赖性方式抑制GABA受体结合。7位碳原子上含有未取代哌嗪基的喹诺酮类化合物具有较强的抑菌活性。具有N-甲基哌嗪基的喹诺酮类化合物抑制活性较弱。Scatchard分析表明，这种抑制GABA受体结合的作用是由于结合容量的降低，而不是受体位点亲和力的改变。鉴于文献报道的使用依诺沙星和非甾体抗炎药芬布芬的患者，我们研究了在各种非甾体抗炎药存在下新喹诺酮类药物对GADA受体结合的影响。除阿司匹林外，新喹诺酮类药物的抑制作用在NSAID的存在下增强。特别是在芬布芬活性代谢产物乙酸联苯存在下，喹诺酮类药物的抑制活性明显增强。根据Scatchard分析，GABA受体结合的这种抑制是由于受体位点的改变。侧脑室注射依诺沙星（10 nmol）不引起小鼠惊厥。然而，当与联苯乙酸（5 nmol），依诺沙星（2.5 nmol）在所有小鼠引起惊厥。从这些结果，这表明，新的喹诺酮类药物可能通过抑制GABA受体结合引起惊厥。新喹诺酮类药物在较低浓度下与NSAIDs合用时可能诱发惊厥。

Since it was reported that new quinolones induced convulsions, we studied the effect of new quinolones on the receptor binding of gamma-aminobutyric acid (GABA),an inhibitory transmitter in the mammalian central nervous system, using mouse synaptic membranes. New quinolones inhibited GABA receptor binding in a concentration-dependent manner. The quinolone, which has unsubstituted piperzinyl group at carbon 7 had stronger inhibitory activity. The quinolone, which had N-methylated piperazinyl group, had weaker inhibitory activity. Scatchard analysis revealed that this inhibition of GABA receptor binding was due to the decrease of binding capacity and not to the change of the affinity of the receptor sites.As it was reported that the patients treated with enoxacin and fenbufen, one of the non-steroidal anti-inflammatory drugs (NSAIDs), we studied the effect of new quinolones on GADA receptor bindings in the presnce of various NSAIDs. The inhibitory effect of new quinolones was enhanced in the presence of NSAIDs, except aspirin. Especially in the presence of biphenyl acetate, an active metabolite of fenbufen, the inhibitory activity of quinolones was remerkably enhanced. According to the Scatchard analysis, this inhibition of GABA receptor binding was due to the change of the receptor sites. And intraventricular injection of enoxacin in mouse brain did not induce convulsions(up to 10 nmol). However, when co-administered with biphenyl acetic acid (5 nmol), enoxacin(2.5 nmol) induced convulsions in all mice.From these results, it was suggested that new quinolones might induce convulsions through the inhibition of GABA receptor binding. And it was also suggested that new quinolones might induce convulsions in their lower concentrations in the presence of NSAIDs.