Pharmacological studies on the novel antiallergic drug HQL-79: II. Elucidation of mechanisms for antiallergic and antiasthmatic effects.
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.
Matsushita
N
N
New Drug Research Department, High Quality-Life Research Laboratories, Sumitomo Metal Industries, Ltd., Kyoto, Japan.
Aritake
K
K
Takada
A
A
Hizue
M
M
Hayashi
K
K
Mitsui
K
K
Hayashi
M
M
Hirotsu
I
I
Kimura
Y
Y
Tani
T
T
Nakajima
H
H
D000818:Animals; D018926:Anti-Allergic Agents / Q000494:pharmacology*; D018927:Anti-Asthmatic Agents / Q000494:pharmacology*; D000941:Antigens / Q000494:pharmacology; D002199:Capillary Permeability / Q000187:drug effects; D003984:Dibenzazepines / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016166:Free Radical Scavengers / Q000494:pharmacology; D006168:Guinea Pigs; D006632:Histamine / Q000494:pharmacology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006636:Histamine Release / Q000187:drug effects; D007082:Ileum / Q000187:drug effects / Q000502:physiology; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D019746:Intramolecular Oxidoreductases / Q000187:drug effects / Q000378:metabolism; D007665:Ketotifen / Q000494:pharmacology; D007975:Leukotriene B4 / Q000378:metabolism; D017997:Leukotriene C4 / Q000378:metabolism; D054834:Lipocalins; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009119:Muscle Contraction / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology*; D015230:Prostaglandin D2 / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012130:Respiratory Hypersensitivity / Q000378:metabolism / Q000503:physiopathology; D012701:Serotonin / Q000494:pharmacology; D012756:Sheep; D012879:Skin Physiological Phenomena / Q000187:drug effects; D014132:Trachea / Q000187:drug effects / Q000502:physiology
C116322:4-benzhydryloxy-1-(3-(1H-tetrazol-5-yl-)-propyl)piperidine; D018926:Anti-Allergic Agents; D018927:Anti-Asthmatic Agents; D000941:Antigens; D003984:Dibenzazepines; D016166:Free Radical Scavengers; D006634:Histamine H1 Antagonists; D007093:Imidazoles; D054834:Lipocalins; D010880:Piperidines; D007975:Leukotriene B4; D017997:Leukotriene C4; D012701:Serotonin; C032727:piperidine; D006632:Histamine; D011451:Prostaglandin-Endoperoxide Synthases; D019746:Intramolecular Oxidoreductases; C022466:prostaglandin R2 D-isomerase; D015232:Dinoprostone; C053090:epinastine; D015230:Prostaglandin D2; D007665:Ketotifen