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