A photoswitchable ligand targeting β1-adrenoceptor enables light-control of the cardiac rhythm

Abstract

SummaryCatecholamine-triggered β-adrenoceptor (β-AR) signaling is essential for the correct functioning of the heart. Although both β1- and β2-AR subtypes are expressed in cardiomyocytes, drugs selectively targeting β1-AR have proven this receptor as the main target for the therapeutic effects of beta blockers in heart. Here, we report a new strategy for the spatiotemporal control of β1-AR activation by means of light-regulated drugs with a high level of β1-/β2-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 alive 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 β1-AR in native environments using light.