Comparative molecular field analysis of the binding of the stereoisomers of fenoterol and fenoterol derivatives to the β2 adrenergic receptor

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

Research output: Contribution to journalArticlepeer-review

Abstract

Stereoisomers of fenoterol and six fenoterol derivatives have been synthesized and their binding affinities for the β2 adrenergic receptor (Kiβ2-AR), the subtype selectivity relative to the β1-AR (Kiβ1-AR/K iβ2-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 Kiβ1-AR/K iβ2-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 Kiβ2 and subtype selectivity.

Original languageEnglish (US)
Pages (from-to)2903-2915
Number of pages13
JournalJournal of medicinal chemistry
Volume50
Issue number12
DOIs
StatePublished - Jun 14 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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