1. Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the beta2 adrenergic receptor
- Author
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Lucita Jimenez, Anthony Y-H Woo, Irving W. Wainer, Weizhong Zhu, Rui Ping Xiao, Mary J. Tanga, Darrell R. Abernethy, Krzysztof Jozwiak, Joseph A. Kozocas, Ilona Berzetei-Gurske, and Chakir Khalid
- Subjects
Male ,Models, Molecular ,Molecular model ,Stereochemistry ,Quantitative Structure-Activity Relationship ,Stereoisomerism ,In Vitro Techniques ,Chemical synthesis ,Cell Line ,Rats, Sprague-Dawley ,Radioligand Assay ,Drug Discovery ,medicine ,Animals ,Humans ,Myocytes, Cardiac ,Binding site ,Adrenergic beta-2 Receptor Agonists ,Fenoterol ,Cerebral Cortex ,Chemistry ,Diastereomer ,respiratory system ,Myocardial Contraction ,Rats ,Molecular Medicine ,Receptors, Adrenergic, beta-2 ,Enantiomer ,Chirality (chemistry) ,medicine.drug - Abstract
Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinities for the beta2 adrenergic receptor (Kibeta2-AR), the subtype selectivity relative to the beta1-AR (Kibeta1-AR/Kibeta2-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 Kibeta1-AR/Kibeta2-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 Kibeta2 and subtype selectivity.
- Published
- 2007