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

Stanek M, Picard LP, Schmidt MF, Kaindl JM, Hübner H, Bouvier M, Weikert D, Gmeiner P

Department of Chemistry and Pharmacy, Medicinal Chemistry , Friedrich-Alexander University Erlangen-Nürnberg (FAU) , Nikolaus-Fiebiger-Str. 10 , Erlangen 91058 , Germany.

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 Gαs, while they only show weak or even no β-arrestin-2 recruitment at both β1- and β2-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 β2-selective, G protein-biased partial agonist salmeterol depends on specific hydrogen bonding between Ser5.46 and Asn6.55, and the aromatic head group of the ligands.

J. Med. Chem. 2019;62(10):5111-5131.

Pubmed ID: 31042379

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