Jpn. J. Pharmacol. 78 (1), 11-22 (1998)

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

Nobutoshi Matsushita (#), Kosuke Aritake, Ayumi Takada, Masanori Hizue, Kumi Hayashi, Kazuhiko Mitsui, Masatoshi Hayashi, Ichiro Hirotsu, Yoshiyuki Kimura, Tadato Tani and Hiromichi Nakajima

New Drug Research Department, High Quality-Life Research Laboratories, Bio-Medical Division, Sumitomo Metal Industries, Ltd., 3-5 Hikaridai, Seika-cho, Souraku-gun, Kyoto 619-0237, Japan
(#) Present address for correspondence: Pharmacological Research Group, Bioclinical Research Division, Rohto Pharmaceutical Co., Ltd., 1-8-1, Tatsumi-nishi, Ikuno-ku, Osaka 544-8666, Japan

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.

Keywords: Antihistamine, Prostaglandin D2, Prostaglandin E2, Prostaglandin D synthase, HQL-79

Copyrightę The Japanese Pharmacological Society 1998

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