5-LIPOXYGENASE INHIBITORY AND ANTIHISTAMINE ACTIVITIES OF LINETASTINE

The ability of linetastine (TMK688, 1-[{5'-(3 ''-methoxy-4 tadienoyl}a minoethyl]-4-diphenylmethoxypiperidine, CAS 110501-66-1) to inhibit le ukotriene production and to antagonize the effect of histamine was exa mined in comparison with the ability of azelastine, an antiallergic dr ug having an antihistamine activity. Linetastine and its active metabo lite TMK777 (1-[{5'-(3 ''-methoxy-4 tadienoyl}aminoethyl]-4-diphenylme htoxypiperidine, CAS 101619-11-8) inhibited the release of leukotriene s B-4 and C-4 from calcium ionophore-stimulated human leukocytes. The respective IC50 values of leukotriene B-4 were 1.2 x 10(-7) mol/l and 8.6 x 10(-8) mol/l, and those of leukotriene C-4 were 1.5 x 10(-7) mol /l and 7.1 x 10(-8) mol/l. Azelastine also inhibited the release of le ukotriene B-4 and C-4, but its IC50 values were higher than 1 x 10(-5) mol/l. Linetastine at 1-10 mg/kg p.o. inhibited the increase in leuko triene B-4 and C-4 production in the lungs during late asthmatic respo nses in actively sensitized guinea-pigs. The effect of 3.2 mg/kg laste d for more than 16 h. Since repeated oral administration of linetastin e, 1 mg/kg once a day for 7 successive days, showed the same inhibitor y effect on the increase in respiratory resistance and the leukotriene production as single oral administration, the effect of linetastine w as neither tachyphylactic nor cumulative. Azelastine at 10 mg/kg had n o effect on the leukotriene production. Linetastine, TMK777 and azelas tine dose-dependently inhibited the histamine-induced contraction of i solated guinea-pig trachea in a noncompetitive manner, the respective pD'(2) values were 7.28, 7.98 and 8.07. Linetastine inhibited histamin e-induced bronchoconstriction dose-dependently at 1-10 mg/kg (p.o) in guinea-pigs, and the effects lasted for more than 24 h. Repeated oral administration of linetastine, 0.32 to 3.2 mg/kg once a day for 7 succ essive days inhibited the histamine-induced bronchoconstriction, the s ame as single oral dosing. Azelastine at 0.32 mg/kg p.o. also showed a ntihistamine activity. In conclusion, linetastine inhibits both the pr oduction of leukotrienes and the effect of histamine at almost the sam e dose and the effects were long lasting.