Pharmacological Studies on the Novel Antiallergic Drug HQL-79: II. Elucidation of Mechanisms for Antiallergic and Antiasthmatic Effects

Abstract

The effects of 4-benzhydryloxy-1-{3-(1H-tetrazol-5-yl)-propyl}piperidine (HQL-79), a newly developed antiallergic drug, on various chemical mediators and on chemical mediator release were investigated. Orally administered HQL-79 strongly inhibited the histamine-induced skin reaction in rats, and histamine- and 5-hydroxytryptamine (5-HT)-induced bronchoconstriction in guinea pigs. HQL-79 inhibited antigen-induced release of leukotriene (LT) B₄, LTC₄, histamine and prostaglandin (PG) D₂ from the chopped lung tissues of actively sensitized guinea pigs. On the other hand, release of PGE₂, one of the bronchoprotective prostanoids, was significantly enhanced by HQL-79. In an in vivo experiment, chronic administration of HQL-79 clearly reduced PGD₂ contents and enhanced PGE₂ contents in the lungs of repeatedly antigen-exposed guinea pigs. In biochemical studies, HQL-79 inhibited mouse spleen PGD synthase in a concentration-dependent manner. None of the antiallergics such as 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-HT effects, chemical mediator release inhibition, PGE₂-release enhancement and PGD synthase inhibition. It is considered, in particular, that the differential modulation of PGD₂ and PGE₂ production is a conspicuous pharmacological feature of HQL-79.