5-Lipoxygenase inhibitory and antihistamine activities of linetastine

The ability of linetastine (TMK688, 1-[¿5'-(3"-methoxy-4"-ethoxycarbonyloxyphenyl)-2',4'-pentadieno yl¿ aminoethyl]-4-diphenylmethoxypiperidine, CAS 110501-66-1) to inhibit leukotriene production and to antagonize the effect of histamine was examined in comparison with the ability of azelastine, an antiallergic drug having an antihistamine activity. Linetastine and its active metabolite TMK777 (1-[¿5'-(3"-methoxy-4"-hydroxyphenyl)-2',4'-pentadienoyl¿ aminoethyl]-4-diphenylmethoxypiperidine, CAS 101619-11-8) inhibited the release of leukotrienes B4 and C4 from calcium ionophore-stimulated human leukocytes. The respective IC50 values of leukotriene B4 were 1.2 x 10(-7) mol/l and 8.6 x 10(-8) mol/l, and those of leukotriene C4 were 1.5 x 10(-7) mol/l and 7.1 x 10(-8) mol/l. Azelastine also inhibited the release of leukotriene B4 and C4, 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 leukotriene B4 and C4 production in the lungs during late asthmatic responses in actively sensitized guinea-pigs. The effect of 3.2 mg/kg lasted for more than 16 b. Since repeated oral administration of linetastine, 1 mg/kg once a day for 7 successive days, showed the same inhibitory effect on the increase in respiratory resistance and the leukotriene production as single oral administration, the effect of linetastine was neither tachyphylactic nor cumulative. Azelastine at 10 mg/kg had no effect on the leukotriene production. Linetastine TMK777 and azelastine dose-dependently inhibited the histamine-induced contraction of isolated guinea-pig trachea in a noncompetitive manner, the respective pD2 values were 7.28, 7.98 and 8.07. Linetastine inhibited histamine-induced bronchoconstriction dose-dependently at 1-10 mg/kg (p.o.) in guinea-pigs, and the effect lasted for more than 24 h. Repeated oral administration of linetastine, 0.32 to 3.2 mg/kg once a day for 7 successive days inhibited the histamine-induced bronchoconstriction, the same as single oral dosing. Azelastine at 0.32 mg/kg p.o. also showed antihistamine activity. In conclusion, linetastine inhibits both the production of leukotrienes and the effect of histamine at almost the same dose and the effects were long lasting.