ARTICLE. Duran Corbera A, Catena J, Otero-Viñas M, Llebaria A, Rovira X. Photoswitchable antagonists for a precise spatiotemporal control of β 2-adrenoceptors. J Med Chem. 2020 Jul 20. doi: 10.1021/acs.jmedchem.0c00831. PMID: 32686936

Abstract.

β2-adrenoceptors (β2-AR) are prototypical G protein-coupled receptors and important pharmacological targets with relevant roles in physiology and disease. Herein, we introduce Photoazolol-1-3, a series of photoswitchable azobenzene β2-AR antagonists that can be reversibly controlled with light. These new photochromic ligands are designed following the azologization strategy, with a p-acetamido azobenzene substituting the hydrophobic moiety present in many β2-AR antagonists. Using a FRET biosensor-based assay, a variety of photopharmacological properties are identified. Two of the light-regulated molecules show potent β2-AR antagonism and enable a reversible and dynamic control of cellular receptor activity with light. Their photopharmacological properties are opposite, with Photoazolol-1 being more active in the dark whereas Photoazolol-2 demonstrates higher antagonism upon illumination. In addition, we provide a molecular rationale for the interaction of the different photoisomers with the receptor. Overall, we present innovative tools and a proof of concept for the precise control of β2-AR by means of light.