A Photoswitchable Ligand Targeting the β1-Adrenoceptor Enables Light-Control of the Cardiac Rhythm

Catecholamine-triggered beta-adrenoceptor (beta-AR) signaling is essential for the correct functioning of the heart. Although both beta(1)- and beta(2)-AR subtypes are expressed in cardiomyocytes, drugs selectively targeting beta(1)-AR have proven this receptor as the main target for the therapeutic effects of beta blockers in the heart. Here, we report a new strategy for the light-control of beta(1)-AR activation by means of photoswitchable drugs with a high level of beta(1)-/beta(2)-AR selectivity. All reported molecules allow for an efficient real-time optical control of receptor function in vitro. Moreover, using confocal microscopy we demonstrate that the binding of our best hit, pAzo-2, can be reversibly photocontrolled. Strikingly, pAzo-2 also enables a dynamic cardiac rhythm management on living zebrafish larvae using light, thus highlighting the therapeutic and research potential of the developed photoswitches. Overall, this work provides the first proof of precise control of the therapeutic target beta(1)-AR in native environments using light.

Automated summary

In this study, a new strategy for light-controlled activation of beta(1)-AR was reported using photoswitchable drugs with high selectivity for beta(1)-/beta(2)-AR. The molecules reported in this study allowed for efficient real-time optical control of receptor function in vitro. The best hit, pAzo-2, showed reversible photocontrol of binding and enabled dynamic cardiac rhythm management on living zebrafish larvae using light.