A Photoswitchable Ligand Targeting the β(1)‐Adrenoceptor Enables Light‐Control of the Cardiac Rhythm

Catecholamine‐triggered β‐adrenoceptor (β‐AR) signaling is essential for the correct functioning of the heart. Although both β(1)‐ and β(2)‐AR subtypes are expressed in cardiomyocytes, drugs selectively targeting β(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 β(1)‐AR activation by means of photoswitchable drugs with a high level of β(1)‐/β(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 β(1)‐AR in native environments using light.