Nielsen S T, Dove P A, Strike D P, Schiehser G A
Wyeth Laboratories, Inc., Philadelphia, PA 19101.
Drugs Exp Clin Res. 1987;13(5):297-304.
Structural analogues (e.g., Wy-46,499) of a known H2-antagonist (Wy-45,662) were found to inhibit acid secretion in the pylorus ligated rat and to block forskolin and DBcAMP-stimulated [14C]amino-pyrine (AP) uptake by rat isolated gastric mucosal cell preparations. Wy-45,662 (N-[3-[3-(1-piperidinylmethyl)phenoxy]propyl]thieno [3,4- d]isothiazol-3-amine 1, 1-dioxide), a very potent histamine H2-antagonist and antisecretory agent in the rat (ED50 approximately equal to 0.3 mg/kg), had no effect in vitro at 1 microM on forskolin-induced [14C]AP uptake while 10 nM Wy-45,662 completely suppressed histamine-stimulated [14C]AP uptake. In contrast, the N-benzylated form of Wy-45,662, Wy-46,499, dose-dependently (1 X 10(-7) -3 X 10(-6)M) suppressed forskolin-stimulated [14C]AP uptake while retaining modest antisecretory activity (ED50 approximately equal to 8 mg/kg) in vivo. Wy-46,499's modest antisecretory activity was thus attributable to inhibition via a post-histamine H2-receptor mechanism.
已知H2拮抗剂（Wy-45,662）的结构类似物（如Wy-46,499）被发现可抑制幽门结扎大鼠的胃酸分泌，并阻断福斯高林和二丁酰环磷腺苷刺激的大鼠离体胃黏膜细胞制剂对[14C]氨基吡啶（AP）的摄取。Wy-45,662（N-[3-[3-(1-哌啶基甲基)苯氧基]丙基]噻吩并[3,4-d]异噻唑-3-胺1,1-二氧化物）是大鼠体内一种非常有效的组胺H2拮抗剂和抗分泌剂（ED50约等于0.3mg/kg），在1μM浓度下对福斯高林诱导的[14C]AP摄取无体外作用，而10nM的Wy-45,662可完全抑制组胺刺激的[14C]AP摄取。相比之下，Wy-45,662的N-苄基化形式Wy-46,499可剂量依赖性地（1×10(-7)-3×10(-6)M）抑制福斯高林刺激的[14C]AP摄取，同时在体内保留适度的抗分泌活性（ED50约等于8mg/kg）。因此，Wy-46,499适度的抗分泌活性归因于通过组胺H2受体后机制的抑制作用。
