Investigation of the Bioactive Conformation of Histamine H_3 ReceptorAntagonists by the Cyclopropylic Strain-Based Conformational Restriction Strategy
Investigation of the Bioactive Conformation of Histamine H_3 ReceptorAntagonists by the Cyclopropylic Strain-Based Conformational Restriction Strategy
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基于环丙基菌株的构象限制策略研究组胺H_3受体拮抗剂的生物活性构象
DOI：
10.1021/jm901848b
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发表时间：
2010
期刊：
影响因子：
--
通讯作者：
S. Shuto
中科院分区：
文献类型：
--
作者：
M. Watanabe;T. Hirokawa;T. Kobayashi;A. Yoshida;Y. Ito;S. Yamada;N. Orimoto;Y. Yamasaki;M. Arisawa;S. Shuto
我们以前鉴定了高效组胺H3受体拮抗剂（1 R，2S）-2-[2-（4-氯苄基氨基）乙基]-1-（1H-咪唑-4-基）环丙烷（1）及其对映体-1。虽然1和1的构象受到中心环丙烷环的限制，但H3受体结合所必需的2-（4-氯苄基氨基）乙基侧链可以自由旋转。为了研究其生物活性构象，以环丙基菌株为基础，设计了1′-乙基取代的衍生物2a和2及其对映异构体2a和2b，作为1和1的侧链构象限制性类似物。合成了这些化合物，通过NMR和计算对它们的分析表明，侧链部分如预期的那样被环丙基菌株有效地限制为α-形式或对映体形式。药理学评价和对接模拟结果表明，1和dent-1的生物活性构象分别为顺式和反式。因此，环丙基菌株可以有效地用于环丙烷化合物的侧链部分的构象限制。
We previously identified the highly potent histamine H3receptor antagonists (1R,2S)-2-[2-(4-chlorobenzylamino)ethyl]-1-(1H-imidazol-4-yl)cyclopropane (1) and its enantiomerent-1. Although the conformations of1andent-1are restricted by the central cyclopropane ring, the 2-(4-chlorobenzylamino)ethyl side chain essential for the H3receptor binding may somewhat freely rotate. To investigate the bioactive conformation, the 1′-ethyl-substituted derivatives2aand2band their enantiomersent-2aandent-2bwere designed as side chain conformation-restricted analogues of1andent-1, based on the cyclopropylic strain. These compounds were synthesized, and their analysis by NMR and calculations suggested that the side chain moiety was effectively restricted in asyn-form or ananti-form by the cyclopropylic strain as expected. Pharmacological evaluation and docking simulation showed that the bioactive conformations of1andent-1appear to be thesyn-form and theanti-form, respectively. Thus, the cyclopropylic strain can be effectively used for conformational restriction of the side chain moiety of cyclopropane compounds.