title: Structure-bias relationships for fenoterol stereoisomers in six molecular and cellular assays at the β2-adrenoceptor.
abstract: 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 β2-adrenoceptor (β2AR) triggers a signal transduction via Gsα and Giα proteins. Here, we examined 12 fenoterol stereoisomers in six molecular and cellular assays. Using β2AR-Gsα and β2AR-Giα fusion proteins, (R,S')- and (S,S')-isomers of 4'-methoxy-1-naphthyl-fenoterol were identified as biased ligands with preference for Gs. G protein-independent signaling via β-arrestin-2 was disfavored by these ligands. Isolated human neutrophils constituted an ex vivo model of β2AR 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 Gs-biased β2AR agonists.
authors.affiliation: Institute for Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625, Hannover, Germany.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Reinartz
authors.forename: Solveig
authors.initials: S
authors.lastname: Kälble
authors.forename: Timo
authors.initials: T
authors.lastname: Littmann
authors.forename: Takeaki
authors.initials: T
authors.lastname: Ozawa
authors.forename: Stefan
authors.initials: S
authors.lastname: Dove
authors.forename: Volkhard
authors.initials: V
authors.lastname: Kaever
authors.forename: Irving W
authors.initials: IW
authors.lastname: Wainer
authors.forename: Roland
authors.initials: R
authors.lastname: Seifert
mesh_terms: D058666:Adrenergic beta-2 Receptor Agonists / Q000737:chemistry / Q000494:pharmacology*; D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D005260:Female; D005280:Fenoterol / Q000737:chemistry / Q000494:pharmacology*; D020558:GTP Phosphohydrolases / Q000378:metabolism; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics / Q000378:metabolism*; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D009504:Neutrophils; D017382:Reactive Oxygen Species / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics / Q000378:metabolism*; D011993:Recombinant Fusion Proteins; D061987:Sf9 Cells; D018411:Spodoptera; D013237:Stereoisomerism
chemical_list: D058666:Adrenergic beta-2 Receptor Agonists; D017382:Reactive Oxygen Species; D018343:Receptors, Adrenergic, beta-2; D011993:Recombinant Fusion Proteins; D005280:Fenoterol; D000242:Cyclic AMP; D020558:GTP Phosphohydrolases; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019205:GTP-Binding Protein alpha Subunits, Gs