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Title

Photoswitchable Antagonists for a Precise Spatiotemporal Control of β2-Adrenoceptors

AuthorsDuran-Corbera, Anna; Catena, Juan Lorenzo; Otero-Viñas, Marta; Llebaría, Amadeu; Rovira, Xavier
KeywordsMolecules
Antagonists
Molecules structure
Light
Receptors
Issue Date20-Jul-2020
PublisherAmerican Chemical Society
CitationJournal of Medicinal Chemistry 63 (15): 8458–8470 (2020)
Abstractβ2-Adrenoceptors (β2-AR) are prototypical G-protein-coupled receptors and important pharmacological targets with relevant roles in physiological processes and diseases. 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 fluorescence resonance energy transfer (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 and Photoazolol-2 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 β2-AR by means of light.
Publisher version (URL)https://doi.org/10.1021/acs.jmedchem.0c00831
URIhttp://hdl.handle.net/10261/224632
DOIhttp://dx.doi.org/10.1021/acs.jmedchem.0c00831
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