Sasho S, Obase H, Ichikawa S, Kitazawa T, Nonaka H, Yoshizaki R, Ishii A, Shuto K
Pharmaceutical Research Laboratories, Kyowa Hakko Kogyo Co., Ltd., Shizuoka-ken, Japan.
J Med Chem. 1993 Mar 5;36(5):572-9. doi: 10.1021/jm00057a007.
Ranitidine (1), the histamine H2-receptor antagonist, has been previously reported to increase gastric emptying and gastric motility by inhibition of acetylcholinesterase (AChE) and enhancement of acetylcholine (ACh) release. In order to obtain potent gastroprokinetic agents, a new series of ranitidine derivatives (5-32) possessing a nitrogen atom instead of a sulfur atom (B) was synthesized and their AChE inhibitory activity and potentiating action on electrically evoked contractions of guinea pig ileum were evaluated. Modification of substituents R1 and R2 markedly influenced the activities. In particular, compound 19, (1-[2-[[[5-(piperidinomethyl)-2-furanyl]methyl]amino]-ethyl]-2- imidazolidinylidene)propanedinitrile fumarate, showed 20 and 100 times more potent AChE inhibitory activity and potentiating action on the ileal contraction, respectively, than ranitidine. Furthermore, compound 19 (KW-5092) enhanced gastrointestinal motility in anesthetized rabbits along with a negligible histamine H2-receptor blocking activity.
雷尼替丁（1），一种组胺H2受体拮抗剂，先前已有报道称它可通过抑制乙酰胆碱酯酶（AChE）和增强乙酰胆碱（ACh）释放来加快胃排空并增强胃动力。为了获得强效的促胃肠动力药物，合成了一系列新型雷尼替丁衍生物（5 - 32），这些衍生物含有一个氮原子而非硫原子（B），并评估了它们对AChE的抑制活性以及对豚鼠回肠电诱发收缩的增强作用。取代基R1和R2的修饰对活性有显著影响。特别是化合物19，（1 - [2 - [[[5 - （哌啶甲基） - 2 - 呋喃基]甲基]氨基] - 乙基] - 2 - 咪唑烷亚基）丙二腈富马酸盐，其对AChE的抑制活性和对回肠收缩的增强作用分别比雷尼替丁强20倍和100倍。此外，化合物19（KW - 5092）可增强麻醉兔的胃肠动力，同时组胺H2受体阻断活性可忽略不计。
