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

Stanek M, Picard LP, Schmidt M, Kaindl J, Hübner H, Bouvier M, Weikert D, Gmeiner P (2019)

Publication Type: Journal article

Publication year: 2019


Book Volume: 62

Pages Range: 5111-5131

Journal Issue: 10

DOI: 10.1021/acs.jmedchem.9b00349


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.

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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://doi.org/10.1021/acs.jmedchem.9b00349


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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