Comparative Molecular Field Analysis of the Binding of the Stereoisomers of Fenoterol and Fenoterol Derivatives to the 
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- 作者：Krzysztof Jozwiak ; Chakir Khalid ; Mary J. Tanga ; Ilona Berzetei-Gurske ; Lucita Jimenez ; Joseph A. Kozocas ; Anthony Woo ; Weizhong Zhu ; Rui-Ping Xiao ; Darrell R. Abernethy ; Irving W. Wainer
- 刊名：Journal of Medicinal Chemistry
- 出版年：2007
- 出版时间：June 14, 2007
- 年：2007
- 卷：50
- 期：12
- 页码：2903 - 2915
- 全文大小：319K
- 年卷期：v.50,no.12(June 14, 2007)
- ISSN：1520-4804
文摘
Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinitiesfor the 
2 adrenergic receptor (Ki2-AR), the subtype selectivity relative to the 1-AR (Ki1-AR/Ki2-AR)and their functional activities were determined. Of the 26 compounds synthesized in the study, submicromolarbinding 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 submicromolarconcentrations in cardiomyocyte contractility tests. The Ki1-AR/Ki2-AR ratios were >40 for (R,R)-fenoteroland the (R,R)-p-methoxy and (R,S)-1-naphthyl derivatives and 14 for the (R,R)-1-napthyl derivative. Thebinding data was analyzed using comparative molecular field analysis (CoMFA), and the resulting modelindicated that the fenoterol derivatives interacted with two separate binding sites and one steric restrictedsite on the pseudo-receptor and that the chirality of the second stereogenic center affected Ki2 and subtypeselectivity.
2 adrenergic receptor (Ki2-AR), the subtype selectivity relative to the 1-AR (Ki1-AR/Ki2-AR)and their functional activities were determined. Of the 26 compounds synthesized in the study, submicromolarbinding 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 submicromolarconcentrations in cardiomyocyte contractility tests. The Ki1-AR/Ki2-AR ratios were >40 for (R,R)-fenoteroland the (R,R)-p-methoxy and (R,S)-1-naphthyl derivatives and 14 for the (R,R)-1-napthyl derivative. Thebinding data was analyzed using comparative molecular field analysis (CoMFA), and the resulting modelindicated that the fenoterol derivatives interacted with two separate binding sites and one steric restrictedsite on the pseudo-receptor and that the chirality of the second stereogenic center affected Ki2 and subtypeselectivity.