Jpn. J. Pharmacol. 86 (1), 55-64 (2001)

VUF-K-8788, a Periphery-Selective Histamine H1 Antagonist With Anti-pruritic Activities

Toshiaki Takizawa1,2,*, Jiro Matsumoto1, Tsutomu Tohma1, Toru Kanke1, Yasushi Wada1, Masafumi Nagao2, Naoki Inagaki2, Hiroichi Nagai2, Min-Qiang Zhang3,# and Henk Timmerman3

1Tokyo Research Laboratories, Pharmaceutical Division, Kowa Company, Ltd., 2-17-43 Noguchi-cho, Higashi-murayama, Tokyo 189-0022, Japan
2Department of Pharmacology, Gifu Pharmaceutical University, Gifu 502-8585, Japan
3Leiden/Amsterdam Center for Drug Research, Division of Medicinal Chemistry, Vrije Universiteit, Amsterdam, The Netherlands

*Corresponding author. FAX: +81-42-395-0312, E-mail:
#Present address: Organon Laboratories, Ltd., Newhouse ML1 5SH, Scotland, UK

Abstract: The pharmacological properties of 7-{3-[4-(2-quinolinylmethyl)-1-piperazinyl]-propoxy}-2,3-dihydro-4H-1,4-benzothiazin-3-one (VUF-K-8788) were investigated in vitro and in vivo. VUF-K-8788 inhibited [3H]-mepyramine from binding to the cell membrane of lung parenchyma (Ki value: 5.0 nM) and the histamine-induced contraction of isolated guinea pig ileum (pA2: 9.71) without affecting ileal contractions induced by acetylcholine, serotonin, KCl and BaCl2. The increase of vascular permeabilities induced by histamine and passive cutaneous anaphylaxis (PCA) in guinea pigs were inhibited by VUF-K-8788 in a dose-dependent fashion (ED50: 0.24 and 0.26 mg/kg, p.o., respectively). Moreover, the anti-histaminic effect of VUF-K-8788 was also observed in rats. In experiments on the effects on the central nervous system, VUF-K-8788 at 1 mg/kg, p.o. hardly antagonized the H1 receptor at all in the cerebral cortex of guinea pigs. VUF-K-8788 inhibited the PCA-induced scratching behavior completely without affecting thiopental-induced sleep in mice. These results suggested that VUF-K-8788 would be useful in the treatment of allergic disorders such as atopic dermatitis and eczema.

Keywords: VUF-K-8788, Antihistaminic, Antiallergic agent, Itch, Central nervous system effect
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