Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias

Beitrag in einer Fachzeitschrift


Details zur Publikation

Autorinnen und Autoren: Stanek M, Picard LP, Schmidt M, Kaindl J, Hübner H, Bouvier M, Weikert D, Gmeiner P
Zeitschrift: Journal of Medicinal Chemistry
Jahr der Veröffentlichung: 2019
Band: 62
Heftnummer: 10
Seitenbereich: 5111-5131
ISSN: 0022-2623


Abstract

Starting from the β-adrenoceptor agonist isoprenaline and beta-blocker carvedilol, we designed and synthesized three different chemotypes of agonist/antagonist hybrids. Investigations of ligand-mediated receptor activation using bioluminescence resonance energy transfer biosensors revealed a predominant effect of the aromatic head group on the intrinsic activity of our ligands, as ligands with a carvedilol head group were devoid of agonistic activity. Ligands composed of a catechol head group and an antagonist-like oxypropylene spacer possess significant intrinsic activity for the activation of Gα
s
, while they only show weak or even no β-arrestin-2 recruitment at both β
1
- and β
2
-AR. Molecular dynamics simulations suggest that the difference in G protein efficacy and β-arrestin recruitment of the hybrid (S)-22, the full agonist epinephrine, and the β
2
-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser
5.46
and Asn
6.55
, and the aromatic head group of the ligands.


FAU-Autorinnen und Autoren / FAU-Herausgeberinnen und Herausgeber

Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie
Kaindl, Jonas
Lehrstuhl für Pharmazeutische Chemie
Schmidt, Maximilian
Lehrstuhl für Pharmazeutische Chemie
Stanek, Markus
Lehrstuhl für Pharmazeutische Chemie
Weikert, Dorothee Dr.
Lehrstuhl für Pharmazeutische Chemie


Einrichtungen weiterer Autorinnen und Autoren

Université de Montréal


Zitierweisen

APA:
Stanek, M., Picard, L.P., Schmidt, M., Kaindl, J., Hübner, H., Bouvier, M.,... Gmeiner, P. (2019). Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias. Journal of Medicinal Chemistry, 62(10), 5111-5131. https://dx.doi.org/10.1021/acs.jmedchem.9b00349

MLA:
Stanek, Markus, et al. "Hybridization of β-Adrenergic Agonists and Antagonists Confers G Protein Bias." Journal of Medicinal Chemistry 62.10 (2019): 5111-5131.

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Zuletzt aktualisiert 2019-04-06 um 16:23