STRUCTURE-EPILEPTOGENICITY RELATIONSHIP OF QUINOLONES WITH SPECIAL REFERENCE TO THEIR INTERACTION WITH GAMMA-AMINOBUTYRIC ACID RECEPTOR-SITES
STRUCTURE-EPILEPTOGENICITY RELATIONSHIP OF QUINOLONES WITH SPECIAL REFERENCE TO THEIR INTERACTION WITH GAMMA-AMINOBUTYRIC ACID RECEPTOR-SITES
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DOI：
10.1128/aac.33.10.1704
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发表时间：
1989-10-01
影响因子：
4.9
通讯作者：
OSADA, Y
中科院分区：
文献类型：
--
作者：
AKAHANE, K;SEKIGUCHI, M;OSADA, Y
探讨了喹诺酮类药物的化学结构与致痫活性的关系。当喹诺酮类药物与口服联苯乙酸同时静脉给药时，非甾体类药物芬布芬、依诺沙星、诺氟沙星、环丙沙星和哌哌甲酯酸的主要代谢产物（在其母核的7位上具有未取代的哌嗪部分）以剂量依赖性方式在6.25 mg/kg或更高的剂量下引起阵挛性惊厥和随后的死亡。AM-1091和T-3262在其7位具有未取代的氨基吡咯烷部分，其致癫痫性低于上述化合物。相比之下，氧氟沙星、AT-4140和萘啶酸（其哌嗪在其7位被甲基取代或没有哌嗪部分）从未诱导惊厥，即使在100 mg/kg剂量下也是如此。然而，洛美沙星含有3-甲基哌嗪，在6.25毫克/公斤或更高的剂量下会引起惊厥。在联苯乙酸的存在下，除萘啶酸外的所有测试喹诺酮竞争性抑制[3 H]蝇蕈醇与γ-受体位点的结合。氨基丁酸（GABA）。即使在测试的最高浓度下，即，10-4 M. [~ 3 H]蝇蕈醇结合的50%抑制剂量在4个数量级或更大的范围内变化，各种化合物的50%抑制剂量在10 ~（-8）M至10 ~（-4）M以上，喹诺酮类的致痫活性与其对[~ 3 H]蝇蕈醇与GABA受体结合的抑制效力之间存在密切的相关性。这些结果表明喹诺酮类药物的致痫活性可能与其7位取代基的GABA样结构有关，它们具有GABA受体拮抗剂的作用。
The relationship between the chemical structure and epileptogenic activity of quinolones was investigated. When the quinolones were administered intravenously to mice concomitantly with oral biphenylacetic acid, a major metabolite of the nonsteroidal antiinflammatory drug fenbufen, enoxacin, norfloxacin, ciprofloxacin, and pipemidic acid, which have an unsubstituted piperazine moiety at the 7 position of their parent nuclei, provoked clonic convulsions and subsequent death at doses of 6.25 mg/kg or more in a dose-dependent manner. AM-1091 and T-3262, which have an unsubstituted aminopyrrolidine moiety at their 7 positions, were less epileptogenic than the compounds listed above were. In contrast, ofloxacin, AT-4140, and nalidixic acid, which have piperazine substituted wiht methyl group(s) or no piperazine moiety at their 7 positions, never induced convulsions, even at doses of 100 mg/kg. Lomefloxacin, which has a 3-methyl piperazine, however, provoked convulsions at doses of 6.25mg/kg or more. In the presence of biphenylacetic acid, all the test quinolones except nalidixic acid competitively inhibited [3H]muscimol binding to receptor sites for .gamma.-aminobutyric acid (GABA) in vitro. Nalidix acid did not inhibit the binding at all, even at the highest concentration tested, i.e., 10-4 M. The 50% inhibition doses for [3H]muscimol binding vaired within 4 orders of magnitude or more, between 10-8 to more than 10-4 M for various compounds, and there was a close correlation between the epileptogenic activities of quinolones and their inhibitory potencies for [3H]muscimol binding to GABA receptor sites. These results indicate that the epileptogenic activity of quinolones possibly relates to the GABA-like structures of substituents at their 7 positions, which act as antagonists of GABA receptors.