PHARMACOLOGICAL STUDIES ON THE NOVEL ANTIALLERGIC DRUG HQL-79 - II - ELUCIDATION OF MECHANISMS FOR ANTIALLERGIC AND ANTIASTHMATIC EFFECTS

The effects of ydryloxy-1-{3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL -79), a newly developed antiallergic drug, on various chemical mediato rs and on chemical mediator release were investigated. Orally administ ered HQL-79 strongly inhibited the histamine-induced skin reaction in rats, and histamine- and 5-hydroxytryptamine (5-HT)-induced bronchocon striction in guinea pigs. HQL-79 inhibited antigen-induced release of leukotriene (LT) B-4, LTC4, histamine and prostaglandin (PG)D-2 from t he chopped lung tissues of actively sensitized guinea pigs. On the oth er hand, release of PGE(2), one of the bronchoprotective prostanoids, was significantly enhanced by HQL-79. In an in vivo experiment, chroni c administration of HQL-79 clearly reduced PGD(2) contents and enhance d PGE(2) contents in the lungs of repeatedly antigen-exposed guinea pi gs. In biochemical studies, HQL-79 inhibited mouse spleen PGD synthase in a concentration-dependent manner. None of the antiallergics such a s epinastine, terfenadine, oxatomide and cetirizine inhibited the PGD synthase. HQL-79 did not affect PGE synthase in sheep vesicular gland microsomes. These results suggest that antiallergic and antiasthmatic effects of HQL-79 could be ascribed to antihistaminic- and anti-5-MT e ffects, chemical mediator release inhibition, PGE(2)-release enhanceme nt and PGD synthase inhibition. It is considered, in particular, that the differential modulation of PGD(2) and PGE(2) production is a consp icuous pharmacological feature of HQL-79.