Structure-bias relationships for fenoterol stereoisomers in six molecular and cellular assays at the β2-adrenoceptor

• Published in: Naunyn-Schmiedeberg's archives of pharmacology Vol. 388; no. 1; pp. 51 - 65
• Main Authors: Reinartz, Michael T., Kälble, Solveig, Littmann, Timo, Ozawa, Takeaki, Dove, Stefan, Kaever, Volkhard, Wainer, Irving W., Seifert, Roland
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01-01-2015
• Subjects: Adrenergic beta-2 Receptor Agonists - chemistry; Adrenergic beta-2 Receptor Agonists - pharmacology; Animals; Biomedical and Life Sciences; Biomedicine; Cyclic AMP - metabolism; Female; Fenoterol - chemistry; Fenoterol - pharmacology; GTP Phosphohydrolases - metabolism; GTP-Binding Protein alpha Subunits, Gi-Go - genetics; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; GTP-Binding Protein alpha Subunits, Gs - genetics; GTP-Binding Protein alpha Subunits, Gs - metabolism; HEK293 Cells; Humans; Male; Neurosciences; Neutrophils; Original Article; Pharmacology/Toxicology; Reactive Oxygen Species - metabolism; Receptors, Adrenergic, beta-2 - genetics; Receptors, Adrenergic, beta-2 - metabolism; Recombinant Fusion Proteins; Sf9 Cells; Spodoptera; Stereoisomerism; β; Functional selectivity; Fenoterol; Structure-bias relationships; Adrenergic receptor; Bias quantification; Biased ligand
• ISSN: 0028-1298; 1432-1912
• DOI: 10.1007/s00210-014-1054-5

Functional selectivity is well established as an underlying concept of ligand-specific signaling via G protein-coupled receptors (GPCRs). Functionally, selective drugs could show greater therapeutic efficacy and fewer adverse effects. Dual coupling of the β
2
-adrenoceptor (β
2
AR) triggers a signal transduction via G
s
α and G
i
α proteins. Here, we examined 12 fenoterol stereoisomers in six molecular and cellular assays. Using β
2
AR-G
s
α and β
2
AR-G
i
α fusion proteins, (
R
,
S’
)- and (
S
,
S’
)-isomers of 4′-methoxy-1-naphthyl-fenoterol were identified as biased ligands with preference for G
s
. G protein-independent signaling via β-arrestin-2 was disfavored by these ligands. Isolated human neutrophils constituted an ex vivo model of β
2
AR signaling and demonstrated functional selectivity through the dissociation of cAMP accumulation and the inhibition of formyl peptide-stimulated production of reactive oxygen species. Ligand bias was calculated using an operational model of agonism and revealed that the fenoterol scaffold constitutes a promising lead structure for the development of G
s
-biased β
2
AR agonists.