Reinartz, Michael T. and Kaelble, Solveig and Littmann, Timo and Ozawa, Takeaki and Dove, Stefan and Kaever, Volkhard and Wainer, Irving W. and Seifert, Roland (2015) Structure-bias relationships for fenoterol stereoisomers in six molecular and cellular assays at the beta(2)-adrenoceptor. NAUNYN-SCHMIEDEBERGS ARCHIVES OF PHARMACOLOGY, 388 (1). pp. 51-65. ISSN 0028-1298, 1432-1912
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | BETA(2) ADRENERGIC-RECEPTOR; G-PROTEIN; FUNCTIONAL SELECTIVITY; FUSION PROTEINS; FIELD ANALYSIS; AGONIST; QUANTIFICATION; DERIVATIVES; MECHANISM; LIGANDS; Functional selectivity; beta(2)-Adrenergic receptor; Biased ligand; Bias quantification; Structure-bias relationships; Fenoterol |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Aug 2019 12:06 |
| Last Modified: | 02 Aug 2019 12:06 |
| URI: | https://pred.uni-regensburg.de/id/eprint/6353 |
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