Design, synthesis, and structure-activity relationships of novel non-imidazole histamine H3 receptor antagonists

被引：60

作者：

Linney, ID ^{[1
]}

Buck, IM ^{[1
]}

Harper, EA ^{[1
]}

Kalindjian, SB ^{[1
]}

Pether, MJ ^{[1
]}

Shankley, NP ^{[1
]}

Watt, GF ^{[1
]}

Wright, PT ^{[1
]}

机构：

[1] James Black Fdn, London SE24 9JE, England

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2000年 / 43卷 / 12期

关键词：

D O I：

10.1021/jm990952j

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Novel, potent, and selective non-imidazole histamine H-3 receptor antagonists have been prepared based on the low-affinity ligand dimaprit (pK(I) 7.32 +/- 0.12, pK(B) 5.93 +/- 0.17). Detailed structure-activity studies have revealed that N-(4-chlorobenzyl)-N-(6-pyrrolidin-1-ylhexyl)guanidine (pK(I) 8.38 +/- 0.21, pK(B) 8.39 +/- 0.13), 30, and N-(4-chlorobenzyl)-N-(7-pyrrolidin-1-ylheptyl)guanidine (pK(I) 8.78 +/- 0.12, pK(B) 8.38 +/- 0.10), 31, exhibit high affinity for the histamine H-3 receptor. Antagonists 30 and 31 demonstrate significant selectivity over the other histamine, H-1 and H-2, receptor subtypes and a 100-fold selectivity in the sigma(1) binding assay. Compounds 30 and 31 are the most potent, selective non-imidazole histamine Ha receptor antagonists reported in the literature to date.

引用

页码：2362 / 2370

页数：9

共 49 条

[1] [H-3]-thioperamide as a radioligand for the histamine H-3 receptor in rat cerebral cortex [J].