Cyclopropane-based conformational restriction of histamine.: (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure
Cyclopropane-based conformational restriction of histamine.: (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane, a highly selective agonist for the histamine H3 receptor, having a cis-cyclopropane structure
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DOI：
10.1021/jm020415q
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发表时间：
2003-05-08
影响因子：
7.3
通讯作者：
Shuto, S
中科院分区：
文献类型：
--
作者：
Kazuta, Y;Hirano, K;Shuto, S
一系列基于环丙烷的组胺构象限制类似物，“折叠”顺式类似物，即，(1S，2 R）-2-（氨甲基）-1-（1H-咪唑-4-基）环丙烷（11），（1 S，2S）-2-（2-氨乙基）-1-（1H-咪唑-4-基）环丙烷（13），及其对映体ent-11和ent-13，以及“扩展的”反式类似物，即，(1R 2 R）-2-（氨甲基）-1-（1H-咪唑-4-基）环丙烷（12）及其对映体ent-12被设计为组胺H-3受体激动剂。这些目标化合物是从多功能手性环丙烷单元（1 S，2 R）-和（1 R，2 R）-2-（叔丁基二苯基硅氧基）甲基-1-甲酰基环丙烷（分别为14和15）或它们的对映体ent-14和ent-15合成的。在构象受限的类似物中，具有顺式环丙烷结构的“折叠”类似物13（AEIC）被鉴定为有效的H-3受体激动剂，其显示出显著的结合亲和力（Ki = 1.31 +/- 0.16 nM）并且对受体具有激动剂作用（EC 50值为10 +/- 3 nM）。这种化合物的重要性在于它是第一种对H-4亚型受体几乎没有影响的高选择性H-3受体激动剂。这些研究表明，顺式环丙烷结构是非常有效的组胺的构象限制，以提高特异性结合组胺H-3受体。
A series of cyclopropane-based conformationally restricted analogues of histamine, the "folded" cis-analogues, i.e., (1S,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (11), (1S,2S)-2-(2-aminoethyl)-1-(1H-imidazol-4-yl)cyclopropane (13), and their enantiomers ent-11 and ent-13, and the "extended" trans-analogues, i.e., (1R,2R)-2-(aminomethyl)-1-(1H-imidazol-4-yl)cyclopropane (12) and its enantiomer ent-12, were designed as histamine H-3 receptor agonists. These target compounds were synthesized from the versatile chiral cyclopropane units, (1S,2R)- and (1R,2R)-2-(tert-butyldiphenylsilyloxy)methyl-1-formylcyclopropane (14 and 15, respectively) or their enantiomers ent-14 and ent-15. Among the conformationally restricted analogues, the "folded" analogue 13 (AEIC) having the cis-cyclopropane structure was identified as a potent H-3 receptor agonist, which showed a significant binding affinity (K-i = 1.31 +/- 0.16 nM) and had an agonist effect (EC50 value of 10 +/- 3 nM) on the receptor. This compound owes its importance to being the first highly selective H-3 receptor agonist to have virtually no effect on the H-4 subtype receptor. These studies showed that the cis-cyclopropane structure is very effective in the conformational restriction of histamine to improve the specific binding to the histamine H-3 receptor.