Optical control of the β2-adrenergic receptor with opto-prop-2: A cis-active azobenzene analog of propranolol

Bosma, Reggie; Dijon, Nicola C.; Zheng, Yang; Schihada, Hannes; Hauwert, Niels J.; Shi, Shuang; Arimont, Marta; Riemens, Rick; Custers, Hans; van de Stolpe, Andrea; Vischer, Henry F.; Wijtmans, Maikel; Holliday, Nicholas D.; Kuster, Diederik W.D.; Leurs, Rob

Abstract

In this study, we synthesized and evaluated new photoswitchable ligands for the beta-adrenergic receptors β1-AR and β2-AR, applying an azologization strategy to the first-generation beta-blocker propranolol. The resulting compounds (Opto-prop-1, -2, -3) have good photochemical properties with high levels of light-induced trans-cis isomerization (>94%) and good thermal stability (t1/2 > 10 days) of the resulting cis-isomer in an aqueous buffer. Upon illumination with 360-nm light to PSScis, large differences in binding affinities were observed for photoswitchable compounds at β1-AR as well as β2-AR. Notably, Opto-prop-2 (VUF17062) showed one of the largest optical shifts in binding affinities at the β2-AR (587-fold, cis-active), as recorded so far for photoswitches of G protein-coupled receptors. We finally show the broad utility of Opto-prop-2 as a light-dependent competitive antagonist of the β2-AR as shown with a conformational β2-AR sensor, by the recruitment of downstream effector proteins and functional modulation of isolated adult rat cardiomyocytes.

Citation

Bosma, R., Dijon, N. C., Zheng, Y., Schihada, H., Hauwert, N. J., Shi, S., …Leurs, R. (2022). Optical control of the β2-adrenergic receptor with opto-prop-2: A cis-active azobenzene analog of propranolol. iScience, 25(9), Article 104882. https://doi.org/10.1016/j.isci.2022.104882

• Journal Article Type: Article
• Acceptance Date: Aug 2, 2022
• Online Publication Date: Sep 16, 2022
• Publication Date: Sep 16, 2022
• Deposit Date: Sep 28, 2022
• Publicly Available Date: Oct 4, 2022
• Journal: iScience
• Electronic ISSN: 2589-0042
• Publisher: Cell Press
• Peer Reviewed: Peer Reviewed
• Volume: 25
• Issue: 9
• Article Number: 104882
• DOI: https://doi.org/10.1016/j.isci.2022.104882
• Keywords: Multidisciplinary
• Public URL: https://nottingham-repository.worktribe.com/output/10920376
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S2589004222011543?via%3Dihub