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

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 (K_i 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.