Photoswitchable Antagonists for a Precise Spatiotemporal Control of β-Adrenoceptors.

β-Adrenoceptors (β-AR) are prototypical G-protein-coupled receptors and important pharmacological targets with relevant roles in physiological processes and diseases. Herein, we introduce , a series of photoswitchable azobenzene β-AR antagonists that can be reversibly controlled with light. These new photochromic ligands are designed following the azologization strategy, with a -acetamido azobenzene substituting the hydrophobic moiety present in many β-AR antagonists. Using a fluorescence resonance energy transfer (FRET) biosensor-based assay, a variety of photopharmacological properties are identified. Two of the light-regulated molecules show potent β-AR antagonism and enable a reversible and dynamic control of cellular receptor activity with light. Their photopharmacological properties are opposite, with being more active in the dark and demonstrating 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 β-AR by means of light.