A Molecular Design Strategy for Light-on Photoswitchable β-Adrenoceptors Agonists with Tailored Photochemical Properties and Distinct Efficacy Profiles

Abstract Despite significant advances in β-adrenoceptor photopharmacology, no photoswitchable agonists have been reported with a fully inactive trans isomer that can be reversibly activated by light. Herein, we present a novel chemical design for the development of light-regulated β1-AR agonists that selectively activate β1-AR upon illumination. Using an azologization strategy based on BI-167107 and Cimaterol, we synthesized and characterized a series of β1-AR-targeting photoswitchable molecules. This approach yielded light-on agonists responsive to both UV and visible light, displaying distinct thermal relaxation kinetics and efficacy profiles. Overall, this study outlines a design strategy that enables the development of drugs targeting these widely studied therapeutic receptors with optimized photochemical and pharmacological properties through structural modification of the core scaffold. These new classes of compounds may serve as future therapeutic agents that can be activated at specific locations and for precisely controlled durations, thereby minimizing off-target effects and systemic side effects.