BMY-40062

The primary target of fluoroquinolones has been identified as the enzyme DNA gyrase, but the mechanism of action of these antibacterial agents is still a matter of controversy. Using partitioning in aqueous polyethylene glycol (PEG)-dextran systems, the affinities of several fluoroquinolones for DNA were determined with accuracy and at equilibrium. It was proved that the binding was strongly dependent on the ability of the drugs to bind Mg2+, with KA values of about 40 000 l mol-1, but was poorly related to the antibacterial activity [minimal inhibitory concentration (MIC) and gyrase inhibition]. Using affinity chromatography on immobilized fluoroquinolone, it was shown that DNA gyrase was unable to bind fluoroquinolones in the absence of DNA, but that a DNA-quinolone-gyrase complex was formed in the presence of Mg2+.

The pharmacological effects of the novel fluoroquinolone 7-(1R,4R-2,5-diazebicyclo[2.2.1]heptan-2-yl)-1-(1,1-dimethyl )ethyl-6-fluoro - 4-oxo-1,4-dihydro-1,8-naphthyridine-3-carboxylic acid (BMY-40062, CAS 116143-32-9) on central nervous system were investigated in mice and rats, in comparison in some cases with those of reference quinolones. BMY-40062 showed no effect on general behavior, spontaneous activity, body temperature and neuromuscular coordination in rats at the doses of 1000 and 250 mg/kg. None of the quinolones tested including BMY-40062 modified the seizures induced by bicuculline, a specific GABA A antagonist. BMY-40062 and ciprofloxacin did not consistently influence the pentetrazol-induced convulsions. On the contrary, pefloxacin exhibited a marked convulsivant activity. In the fenbufen (non-steroidal anti-inflammatory drug)-induced seizure model, BMY-40062 showed no effect. Enoxacin, norfloxacin followed by ciprofloxacin elicited a convulsivant effect in presence of fenbufen. Under these experimental conditions, BMY-40062 had no effect on the central nervous system compared to the other tested quinolones in rodents.