Structure-epileptogenicity relationship of quinolones with special reference to their interaction with gamma-aminobutyric acid receptor sites

Abstract

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 with 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 6.25 mg/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 y-aminobutyric acid (GABA) in vitro. Nalidixic 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 varied 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.

Quinolones: a class of antimicrobial agents

“…These signs subsided within several minutes in the affected dogs, and slower infusion (for 2-3 minutes) did not produce such severe clinical signs. Others (Akahane et al, 1989) reported that the epileptogenic activity of fluoroquinolones possibly relates to the γ-aminobutyric acid (GABA)-like structures of the substituents at position 7 of some of the fluoroquinolones, which may allow them to act as GABA-receptor antagonists. Furthermore, enrofloxacin has increased the frequency and intensity of seizures in epileptic dogs (Van Cutsem et al, 1990).…”

Association between oral fluoroquinolones and seizures

“…[2][3][4][5][6][7][8][9][10][11] Concerns were raised about the safety of FQs on the central nervous system. Although some studies have explored the potential mechanisms of FQ-induced seizure, [12][13][14][15] comprehensive epidemiologic data from populationbased studies are needed. The primary objective of this study was to investigate the relationship between FQs and incident seizures using data from Hong Kong (HK) and the United Kingdom (UK).…”

Norfloxacin-Induced Electroencephalogram Alteration and Seizures in Rats Are Not Triggered by Enhanced Levels of Intracerebral Glutamate

“…It is usually asserted that these excitatory side effects result from inhibition of GABA (␥-aminobutyric acid) binding to its receptors (1,11). Using intracerebral microdialysis, however, Smolders et al have previously observed in conscious rats norfloxacin-induced convulsions accompanied not by any apparent effect on the extracellular hippocampal GABA levels but rather by enhanced intracerebral glutamate concentrations (10).…”