摘要：SummaryIn 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-inducedtrans-cisisomerization (>94%) and good thermal stability (t1/2 > 10 days) of the resultingcis-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.Graphical abstractDisplay OmittedHighlights•A photoswitchable antagonist of the β2-AR was developed: Opto-prop-2•β2-AR binding affinity of the light-inducedcis-Opto-prop-2 is 578-fold stronger•Opto-prop-2 allowed dynamic control of β2-AR antagonism•Opto-prop-2 allowed light-dependent modulation of cardiomyocyte functionPhotomedicine; Biochemical engineering; Biochemical research method
