General pharmacological properties of the main metabolite of flosequinan
Fujita, S.; Ikezono, K.; Umezato, M.; Hosoki, E.; Toba, Y.; Ishikawa, M.; Kusunoki, A.; Shintani, S.
Arzneimittel-Forschung 42(10): 1212-1222
1992
ISSN/ISBN: 0004-4172 PMID: 1335257 Document Number: 393814
The general pharmacological profile of 7-fluoro-1-methyl-3-(methylsulfonyl)-4-(1H)-quinolone (BTS 53 554, CAS 76568-68-8), the main metabolite of a new vasodilator, flosequinan (BTS 49 465), was investigated. The central nervous system: BTS 53 554 at the dose of 30 mg/kg i.v. caused an increase in respiratory rate and a sedation in general behavior in rats. The drug also inhibited acetic acid-induced writhing and slightly decreased normal body temperature in mice. However, the drug at the doses up to 30 mg/kg i.v. had little effect on the spontaneous movement, hexobarbital-induced hypnosis, reserpine-induced hypothermia and motor coordination in mice. The drug showed neither anticonvulsant nor analgesic actions in mice. Furthermore, it had no effect on the spontaneous EEG, sleep-wakefulness cycle and EEG arousal response in rabbits at doses up to 10 mg/kg intravenously. The somatic nervous system: BTS 53 554 induced no muscle relaxation in mice and exerted no local anesthetic action in guinea pigs by corneal reflex method. In addition, it had little effect on the neuromuscular transmission in cats. The autonomic nervous system and smooth muscle: BTS 53 554 showed no effect on the sympathetic ganglionic transmission in cats. In isolated smooth muscles, at doses up to 101-3 mol/l it showed little effect on the acetylcholine- or barium chloride-induced contraction of guinea-pig ileum, norepinephrine-induced contraction of rat vas deferens or oxytocin-induced contraction of non-pregnant rat uterus. However, it inhibited non-competitively norepinephrine-induced contraction of isolated rat aorta at 10-4 mol/l or more and serotonin-induced contraction of isolated rat fundus at 3 times 10-4 mol/l or more. In the isolated guinea-pig ileum, the drug slightly inhibited the histamine-induced maximal contraction at 10-3 mol/l. These results suggest BTS 53 554 had no specific effect on norepinephrine, serotonin, acetylcholine or histamine. The drug relaxed isolated guinea-pig trachea at 3 times 10-5 mol/l or more and inhibited the spontaneous movement of isolated pregnant rat uterus at 10-4 mol/l or more, although these actions were extremely weaker than those of isoproterenol (isoprenaline). BTS 53 554 also showed a slight inhibition of uterus movement in anesthetized rats at 30 mg/kg intravenously. The digestive system: BTS 53 554 tended to inhibit the gastrointestinal propulsion in mice and showed a slight inhibition of gastric and intestinal motilities in rats at 10 mg/kg intravenously. In isolated rabbit ileum, the drug slightly inhibited the spontaneous movement at 3 times 10-3 mol/l. For the gastric secretion in rats, BTS 53 554 at 30 mg/kg i.v. tended to inhibit the secretion, however, the drug increased the pancreatic juice secretion in dogs at 3 and 10 mg/kg intravenously. It showed no effect on the bile secretion in dogs. Other properties: BTS 53 554 at 30 mg/kg i.v. decreased the urine volume and urinary excretion of electrolytes (Na+ and Cl-) in rats. However, it had little effect on the carrageenin-induced edema and the blood coagulation system and did not show hemolytic and local irritative actions. These results suggested BTS 53 554 had little effect on the central and peripheral nervous systems, digestive system and peripheral organs except for its vascular and tracheal smooth muscle relaxant actions and secreto-motor activity on pancreatic juice.