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

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.