期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 63, 期 15, 页码 8458-8470出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.0c00831
关键词
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资金
- la Caixa Foundation [100010434, LCF/BQ/DE18/11670012]
- FEDER/Ministerio de Ciencia, Innovacion y Universidades-Agencia Estatal de Investigacion [CTQ2017-89222-R]
- Catalan Government [2017SGR1604]
- PO FEDER of Catalonia 2014-2020 (project PECT Osona Transformacio Social) [001-P-000382]
- Spanish Ministry of Economy, Industry and Competitiveness [SAF2015-74132-JIN]
beta(2)-Adrenoceptors (beta(2)-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 beta(2)-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 beta(2)-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 beta(2)-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 beta(2)-AR by means of light.
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