Probing the Existence of a Metastable Binding Site at the β2-Adrenergic Receptor with Homobivalent Bitopic Ligands

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Birgit I Gaiser, Mia Danielsen, Emil Marcher-Rørsted, Kira Røpke Jørgensen, Tomasz M Wróbel, Mikael Frykman, Henrik Johansson, Hans Bräuner-Osborne, David E Gloriam, Jesper Mosolff Mathiesen, Daniel Sejer Pedersen

Herein, we report the development of bitopic ligands aimed at targeting the orthosteric binding site (OBS) and a metastable binding site (MBS) within the same receptor unit. Previous molecular dynamics studies on ligand binding to the β2-adrenergic receptor (β2AR) suggested that ligands pause at transient, less-conserved MBSs. We envisioned that MBSs can be regarded as allosteric binding sites and targeted by homobivalent bitopic ligands linking two identical pharmacophores. Such ligands were designed based on docking of the antagonist (S)-alprenolol into the OBS and an MBS and synthesized. Pharmacological characterization revealed ligands with similar potency and affinity, slightly increased β2/β1AR-selectivity, and/or substantially slower β2AR off-rates compared to (S)-alprenolol. Truncated bitopic ligands suggested the major contribution of the metastable pharmacophore to be a hydrophobic interaction with the β2AR, while the linkers alone decreased the potency of the orthosteric fragment. Altogether, the study underlines the potential of targeting MBSs for improving the pharmacological profiles of ligands.

Original languageEnglish
JournalJournal of Medicinal Chemistry
Volume62
Issue number17
Pages (from-to)7806-7839
Number of pages34
ISSN0022-2623
DOIs
Publication statusPublished - 12 Sep 2019

ID: 227411763