Kazuta Yuji, Hirano Kazufumi, Natsume Kentaro, Yamada Shizuo, Kimura Ryohei, Matsumoto Shun-Ichiro, Furuichi Kiyoshi, Matsuda Akira, Shuto Satoshi
Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan.
J Med Chem. 2003 May 8;46(10):1980-8. doi: 10.1021/jm020415q.
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 (EC(50) 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.
设计了一系列基于环丙烷的组胺构象受限类似物，即“折叠”的顺式类似物，如(1S,2R)-2-(氨甲基)-1-(1H-咪唑-4-基)环丙烷(11)、(1S,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“伸展”的反式类似物，如(1R,2R)-2-(氨甲基)-1-(1H-咪唑-4-基)环丙烷(12)及其对映体ent-12，作为组胺H(3)受体激动剂。这些目标化合物由通用的手性环丙烷单元(1S,2R)-和(1R,2R)-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)或其对映体ent-14和ent-15合成。在构象受限类似物中，具有顺式环丙烷结构的“折叠”类似物13(AEIC)被鉴定为一种有效的H(3)受体激动剂，它对该受体显示出显著的结合亲和力(K(i)=1.31±0.16 nM)并具有激动剂效应(EC(50)值为10±3 nM)。该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，顺式环丙烷结构在组胺的构象限制中非常有效，可改善与组胺H(3)受体的特异性结合。
