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.

A study was made of the correlation between the in vitro inhibitory effects of several quinolones, including four ofloxacin derivatives, on bacterial DNA gyrase from Escherichia coli KL-16 and on topoisomerase II from fetal calf thymus. No correlation was observed between the inhibitions of DNA gyrase activity and topoisomerase II activity. On the other hand, the inhibitory effects of these quinolones against topoisomerase II were closely correlated with their inhibition of cell growth. Furthermore, among the oxazine derivatives tested, the derilvative with a methyl group at position 3 in an S configuration showed the highest activity against DNA gyrase and derivatives without a methyl group on the oxazine ring were more potent against topoisomerase H than those with a methyl group. Among these derivatives, DR-3355, the S isomer o1 ofloxacin, showed the highest activity against DNA gyrase and low activity against topoisomerase II. These results indicate that the methyl group on the oxazine ring plays an important role in the inhibitory activities of ofloxacin derivatives for these enzymes.Quinolone antibacterial agents are currently used for the therapy of various bacterial infections. These agents interfere with the activity of DNA gyrase (3-5), and their inhibitory activities against DNA gyrase have been shown to correlate well with their antimicrobial activities (2, 10, 11). Regarding the relationships among the quinolone molecule, DNA gyrase~,.and DNA, proposed a ternary complex model for gyrase inhibition by quinolones. Quinolone molecules bind to the staggered 4 bp at the DNA gyrase cleavage site. It is thought that inhibitory mechanisms should also be active against mammalia jtop6isomer-ase II, but the degree of inhibitory activity shoWn against mammalian topoisoilerase II is less than that seen against DNA gyrase (11, 12, i4). On the basis of these observations, quinolones should have an inhibitory potency against the proliferation of mammal'iah cells. Actually, some quinolones have inhibitory potencies against HeLa cells, leukemic cell lines, and bone marrow cells (1,9,15,16,21,22). Oomori et al. (15) reported that the inhibitory activities of quinolones against topoisomerase II from HeLa cells correlated with their inhibitory potencies against growth of those cells. To select compounds that are more potent against bacteria and less active against mammalian cells, we examined the selective toxicities of many quinolone derivatives to DNA gyrase and topoisomerase II (11). In this study we focused on the inhibitory activities of quinolones, especially ofloxacin (OFLX) derivatives, against DNA gyrase and topoisomerase II from fetal calf thymus and against the proliferation of normal murine CFU-GM (CFU of granulocyte-macrophage progenitor cells), and we determined the structure-activity relationship of the OFLX derivatives. MATERIALS AND METHODSChemicals. OFLX (17) and OFLX derivatives DR-3355 (8), DR-3354 (8), DN-9494, and DL-8165 were synthesized in * Corresponding author. our laboratories, and the structu...

We studied the effects of 'y-aminobutyric acid (GABA)-benzodiazepine receptor agonists and glutamate receptor antagonists on levofloxacin (LVFX)-and ciprofloxacin (CPFX)-induced convulsions using intrathecal (i.t.) injections in mice. We also studied the effects of these agonists and antagonists on exacerbated convulsions induced by coadministration of the quinolone with 4-biphenylacetic acid (BPAA). The agonists or antagonists were injected i.t. 5 min and BPAA was administered orally 30 min before a single i.t. injection of the quinolone (10 pl per animal). The animals were observed for clonic convulsion and death, and latency times to the appearance of convulsion were determined. Among the agonists, baclofen showed marked inhibition of both LVFX-and CPFX-induced convulsions, while other compounds such as GABA, muscimol, diazepam, and 3-aminopropylphosphonic acid had slight effects. Among the antagonists, kynurenic acid showed the strongest inhibition of convulsions caused by all doses of LVFX and CPFX and prolonged latency times; 'y-glutamylaminomethylsulfonic acid (GAMS) also markedly inhibited convulsions. The antagonists D-AP-5, AP-7, and 6,7-dinitroquinoxaline-2,3-dione (DNQX) had slight effects. Additionally, GAMS, DNQX, and MK-801 significantly lowered the incidence of death in the groups treated with CPFX. The enhanced convulsive activities of LVFX or CPFX by pretreatment with BPAA were clearly blocked by baclofen, kynurenic acid, GAMS, and DNQX. D-AP-5 and AP-7 also showed clear effects on the activity of LVFX. These results suggest that LVFX has fewer effects on the brain than CPFX and that convulsions induced by these quinolones alone and by these quinolones administered with BPAA may be mediated largely through glutamate and GABAB rather than GABAA receptors in mice.Because of their excellent activities, quinolone antibacterial agents have been widely adopted for use in clinical practice. Although recently developed quinolones are less toxic than earlier compounds, they still produce very few incidences of various adverse effects on the central nervous system. Among these, convulsions remain a serious problem; enoxacin (ENX) (29), norfloxacin (NFLX) (2, 39), and ciprofloxacin (CPFX) (3) have been reported to induce convulsions in humans. Furthermore, these convulsions have been reported to be enhanced by coadministration with nonsteroidal anti-inflammatory drugs (NSAIDs) (2,3,29,31). The mechanisms underlying these convulsions have therefore been investigated in animal models.It (1, 6, 14, 26-28, 33, 40). Moreover, their enhanced convulsive activity in the presence of NSAIDs is thought to be mediated through the augmentation of interactions between quinolones and GABAA by NSAIDs, as evidenced by electrophysiological studies (10, 18) and binding assays (7). In contrast, other studies have reported the failure of GABA-benzodiazepinergic drugs to inhibit completely convulsions caused by coadministration of a quinolone and an NSAID (11,20,30,31), the lack of any clear correlation between the activitie...

A camptothecin derivative, 7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin (CPT-11), shows a potent antitumour activity in experimental tumour models and in clinical trials. However, CPT-11 induced early diarrhoea and vomiting at high dose levels in clinical studies and showed an acetylcholine-like action on the guinea-pig ileum and trachea. In the present study, we investigated the activities of camptothecin derivatives in inhibiting acetylcholinesterase (AChE) and in binding to muscarinic acetylcholine receptors (AChR). CPT-11 inhibited AChE and binding of the specific ligand to AChR with respective 50% inhibition concentrations of 0.2 and 5 microM. These inhibitions were induced by camptothecin derivatives having an amino group at the C-10 position (or the C-4 position of hexacyclic derivatives), but were not or were only slightly induced by the others. Early defecation and vomiting in dogs were observed after intravenous injection of DU-6596 and DU-6888, two hexacyclic derivatives having the aminomethyl group at the C-4 position, and of CPT-11. DU-6174, however, which has a hydroxy group at this position, induced no early defecation and little vomiting. Plasma concentrations of CPT-11, DU-6596 and DU-6888 after intravenous treatment at doses causing such early adverse effects were maintained for 1 h or longer at levels sufficient to inhibit AChE. These results suggest that the inhibition of AChE by camptothecin derivatives with an amino group at the C-10 position (or the C-4 position) relates to the early defecation or diarrhoea and vomiting.

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 'y-aminobutyric acid (GABA) receptors. The mechanisms of these drug interactions were further examined. Scatchard analysis of[3lH]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-,y-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. 'H 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.The widespread use of new fluorinated quinolones such as ofloxacin, norfloxacin, enoxacin, and ciprofloxacin in the treatment of various bacterial infections has proven to be very effective. The effect of quinolones on the central nervous system (CNS), however, is a common adverse reaction; symptoms include headache, dizziness, and restlessness (10,15,17,23). Although a variety of studies regarding the CNS effects of quinolones have already been conducted, it is difficult, at least for technical reasons, to show which nerve systems are primarily involved in these adverse reactions. While the incidences of CNS side effects are quite low, seizures have been observed more frequently in patients receiving quinolones in combination with nonsteroidal anti-inflammatory drugs such as fenbufen (5,7,30). This drug combination inhibits the binding of -y-aminobutyric acid (GABA) to its receptors (27, 33) and thereby abolishes GABA-induced electrophysiological changes, such as those involving chloride currents in the cerebral nerve cells (4, 16) and electroretinograms (36) of experimental animals. Therefore, the inhibition of the GABA receptors induced by quinolones would be expected to cause general CNS excitation (27,33). However, the mechanism of synergistic binding inhibition of quinol...