Development of histamine H_3 receptor selective ligands based on the versatile chiral cyclopropane units.

高选择性的H_3受体激动剂和拮抗剂不仅是药理学研究的重要工具，而且是新药开发的重要先导。我们设计了一系列基于环丙烷的构象受限的组胺类似物，这些类似物是由我们以前开发的手性环丙烷单元有效地合成的。在这些受构象限制的类似物中，具有顺式环丙烷结构的（1 S，2S）-2-（2-氨乙基）-1-（1H-咪唑-4-基）环丙烷被鉴定为高度H_3选择性激动剂。在此基础上，设计了环丙烷类H_3选择性拮抗剂。这些化合物是通过在已发现的H_3选择性激动剂的结构中引入芳环而设计的，因为在激动剂的适当位置引入芳环有时会使其转化为相应的拮抗剂，这被认为是“伞形效应”。利用这些手性环丙烷单元合成了该类化合物，并发现了一些很强的H_3受体选择性拮抗剂，因此，我们利用这些多功能的手性环丙烷单元，在理论设计的基础上，成功地开发了H_3受体选择性激动剂和拮抗剂。

Highly selective H_3 agonists and also antagonists would not only be very useful as tools for pharmacological studies but would also be important as leads for the development of new drugs. We designed a series of cyclopropane-based conformationally restricted analogues of histamine, which were effectively synthesized from chiral cyclopropane units previously developed by us. Among these conformationally restricted analogues, (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane having the cis-cyclopropane structure was identified as a highly H_3-selective agonist. On the basis of these findings, cyclopropane-based H_3 selective antagonists were designed. These were designed by introducing an aromatic ring into the structure of the H_3 selective agonists found, since introduction of aromatic rings into the proper site of an agonist sometimes convert it into the corresponding antagonist, which has been recognized as "umbrella effect". These compounds were also synthesized from above chiral cyclopropane units, and some very strong H_3 receptor antagonists with selectivity were found. Thus, we successfully developed H_3 selective agonists and antagonists based on theoretical design using the versatile chiral cyclopropane units.