Ganellin C R, Fkyerat A, Hosseini S K, Khalaf Y S, Piripitsi A, Tertiuk W, Arrang J M, Garbarg M, Ligneau X, Schwartz J C
Department of Chemistry, Christopher Ingold Laboratories, University College, London, UK.
J Pharm Belg. 1995 Mar-Jun;50(2-3):179-87.
Starting from thioperamide, the first potent and selective H3-receptor histamine antagonist, analogues have been synthesised and tested in vitro on rat cerebral cortex to explore structure-activity relationships. The aim has been to design compounds which do not possess the thiourea group of thioperamide and which may have improved brain penetration. Some compounds derived from histamine and possessing an aromatic nitrogen-containing heterocycle on the side-chain amino group show strong H3-antagonist activity. These have served as leads to provide aryloxyethyl- and aryloxy-propylimidazoles which are potent H3 antagonists of histamine. Structure-activity studies of the very potent and selective agonist, imetit (S-[2-imidazol-4-yl)ethyl]isothiourea), have explored the the transition between agonist, partial agonist and antagonist. The isosteric isourea is also a potent agonist. N,N'-Dibutyl-[S-[3-(imidazol-4-yl)propyl]isothiourea is a very potent antagonist having Ki = 1.5 nM.
从首个强效选择性H3受体组胺拮抗剂硫代酰胺开始，已合成了其类似物并在大鼠大脑皮层上进行了体外测试，以探索构效关系。目的是设计出不具有硫代酰胺硫脲基团且可能具有改善脑渗透性的化合物。一些源自组胺且在侧链氨基上带有含氮芳香杂环的化合物表现出很强的H3拮抗剂活性。这些化合物已作为先导物，用于提供芳氧基乙基和芳氧基丙基咪唑，它们是强效的组胺H3拮抗剂。对非常强效且选择性的激动剂碘甲磺隆（S-[2-咪唑-4-基）乙基]异硫脲）的构效研究，探索了激动剂、部分激动剂和拮抗剂之间的转变。等排异硫脲也是一种强效激动剂。N，N'-二丁基-[S-[3-（咪唑-4-基）丙基]异硫脲是一种非常强效的拮抗剂，其Ki = 1.5 nM。
