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 beta(2)-adrenoceptor (beta(2)AR) triggers a signal transduction via G(s)alpha and G(i)alpha proteins. Here, we examined 12 fenoterol ...
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 beta(2)-adrenoceptor (beta(2)AR) triggers a signal transduction via G(s)alpha and G(i)alpha proteins. Here, we examined 12 fenoterol stereoisomers in six molecular and cellular assays. Using beta(2)AR-G(s)alpha and beta(2)AR-G(i)alpha 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 beta-arrestin-2 was disfavored by these ligands. Isolated human neutrophils constituted an ex vivo model of beta(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 beta(2)AR agonists.
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