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

自从新喹诺酮类药物引起惊厥的报道以来，我们利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抑制性递质γ-氨基丁酸(GABA)受体结合的影响。新的喹诺酮类药物以浓度依赖的方式抑制GABA受体结合。7碳未取代哌嗪基喹诺酮类化合物具有较强的抑制活性。含有N-甲基化哌嗪基团的喹诺酮类药物的抑菌活性较弱。Scatchard分析表明，这种抑制GABA受体结合的作用是由于受体结合容量的降低，而不是受体亲和力的改变。有报道称，非类固醇抗炎药之一的依诺沙星和芬布芬治疗的患者，我们研究了新的喹诺酮类药物对不同NSAIDs情况下GADA受体结合的影响。除阿司匹林外，新喹诺酮类药物对NSAIDs的抑制作用增强。特别是在芬布芬的活性代谢物乙酸联苯酯的存在下，喹诺酮类药物的抑制活性显著增强。根据Scatchard分析，这种对GABA受体结合的抑制是由于受体位置的改变所致。脑室注射依诺沙星不引起小鼠惊厥(高达10nmoL)。然而，当依诺沙星(2.5nmol)与联苯乙酸(5nmol)联合给药时，可引起小鼠惊厥，提示新喹诺酮类药物可能通过抑制GABA受体的结合而诱发惊厥。也有人建议，新的喹诺酮类药物可能会在较低浓度的非甾体抗炎药存在的情况下诱发惊厥。

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.