Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the β2 adrenergic receptor
Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the β2 adrenergic receptor
复制标题
DOI：
10.1021/jm070030d
复制
发表时间：
2007-06-14
影响因子：
7.3
通讯作者：
Wainer, Irving W.
中科院分区：
文献类型：
--
作者：
Jozwiak, Krzysztof;Khalid, Chakir;Wainer, Irving W.
合成了非诺特罗和6个非诺特罗衍生物的立体异构体，测定了它们与β(2)肾上腺素能受体(K-Iβ(2)-AR)的结合亲和力、相对于β(1)-AR的亚型选择性(K-I beta(1)-AR/K-I beta(2)-AR)及其功能活性。在所合成的26个化合物中，对甲氧基的(R，R)-异构体(R，R)-非诺特罗和1-萘衍生物的(R，R)-和(R，S)-异构体具有亚微摩尔结合亲和力，所有这些化合物在亚微摩尔浓度下都具有心肌细胞收缩活性。(R，R)-非诺特罗和(R，R)-对甲氧基和(R，S)-1-萘衍生物的K-Iβ(1)-AR/K-Iβ(2)-AR比值为>；40，(R，R)-1-萘基衍生物为14。用比较分子场分析(CoMFA)对结合数据进行分析，结果表明非诺特罗衍生物与伪受体上的两个独立的结合部位和一个空间限制部位相互作用，第二立体中心的手性影响K-Iβ(2)和亚型的选择性。
Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinities for the beta(2) adrenergic receptor (K-i beta(2)-AR), the subtype selectivity relative to the beta(1)-AR (K-i beta(1)-AR/K-i beta(2)-AR) and their functional activities were determined. Of the 26 compounds synthesized in the study, submicromolar binding affinities were observed for (R,R)-fenoterol, the (R,R)-isomer of the p-methoxy, and (R,R)- and (R,S)-isomers of 1-naphthyl derivatives and all of these compounds were active at submicromolar concentrations in cardiomyocyte contractility tests. The K-i beta(1)-AR/K-i beta(2)-AR ratios were > 40 for (R,R)-fenoterol and the (R,R)-p-methoxy and (R,S)-1-naphthyl derivatives and 14 for the (R,R)-1-napthyl derivative. The binding data was analyzed using comparative molecular field analysis (CoMFA), and the resulting model indicated that the fenoterol derivatives interacted with two separate binding sites and one steric restricted site on the pseudo-receptor and that the chirality of the second stereogenic center affected K-i beta(2) and subtype selectivity.