Watanabe Mizuki, Kobayashi Takaaki, Ito Yoshihiko, Fukuda Hayato, Yamada Shizuo, Arisawa Mitsuhiro, Shuto Satoshi
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
Bioorg Med Chem Lett. 2018 Dec 15;28(23-24):3630-3633. doi: 10.1016/j.bmcl.2018.10.041. Epub 2018 Oct 26.
We previously designed and synthesized a series of histamine analogues with an imidazolylcyclopropane scaffold and identified potent non-selective antagonists for histamine H and H receptor subtypes. In this study, to develop H selective ligands, we newly designed and synthesized cyclopropane-based derivatives having an indole, benzimidazole, or piperazine structure, which are components of representative H selective antagonists such as JNJ7777120 and JNJ10191584. Among the synthesized derivatives, imidazolylcyclopropanes 12 and 13 conjugated with a benzimidazole showed binding affinity to the H and H receptors comparable to that of a well-known non-selective H/H antagonist, thioperamide. These results suggest that the binding modes of the cyclopropane-based H/H ligands in the H receptor can be different from those of the indole/benzimidazole-piperazine derivatives.
我们之前设计并合成了一系列带有咪唑基环丙烷支架的组胺类似物，并鉴定出了针对组胺H和H受体亚型的强效非选择性拮抗剂。在本研究中，为了开发H选择性配体，我们新设计并合成了具有吲哚、苯并咪唑或哌嗪结构的基于环丙烷的衍生物，这些结构是代表性H选择性拮抗剂（如JNJ7777120和JNJ10191584）的组成部分。在合成的衍生物中，与苯并咪唑共轭的咪唑基环丙烷12和13对H和H受体的结合亲和力与著名的非选择性H/H拮抗剂硫代哌酰胺相当。这些结果表明，基于环丙烷的H/H配体在H受体中的结合模式可能与吲哚/苯并咪唑-哌嗪衍生物不同。
