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

In this study, we synthesized and evaluated new photoswitchable ligands for the beta-adrenergic receptors beta(1)-AR and beta(2)-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 (t(1/2 )> 10 days) of the resulting cis-isomer in an aqueous buffer. Upon illumintion with 360-nm light to PSScis, large differences in binding affinities were observed for photoswitchable compounds at beta(1) -AR as well as beta(2)-AR. Ratably, Opto-prop-2 (VUF17062) showed one of the largest optical shifts in binding affinities at the beta(2)-AR (587-fold, cis-active), as recorded so far for photoswitches of G proteincoupled receptors. We finally show the broad utility of Opto-prop-2 as a light-dependent competitive antgonist of the beta(2)-AR as shown with a conformational beta(2)-AR sensor, by the recruitment of downstream effector proteins and functional modulation of isolated adult rat cardiomyocytes.

Automated summary

In this study, new photoswitchable ligands were synthesized and evaluated for beta-adrenergic receptors with good photochemical properties. Opto-prop-2 showed the largest optical shift at beta(2)-AR, indicating its potential broad utility.