The Might of Light: Optical Control of β-Adrenergic Signaling

Photopharmacology combines photochemistry with pharmacology to enable optical modulation of biological targets using photoresponsive molecules. The use of light to modulate biological processes offers high spatial and temporal precision, potentially reducing on-target side effects. G protein-coupled receptors (GPCRs) are the largest class of pharmaceutical target proteins and are targeted by around 36% of market drugs. As an important member of GPCRs, β-ARs are among the most popular drug targets. Typical β-AR drugs may induce on-target side effects by acting on β-ARs elsewhere in the body. Photopharmacology tools offer enhanced spatiotemporal resolution, leveraging the advantages of light such as safe delivery, reversibility and precise intensity control. This thesis describes the development and characterization of azobenzene-based photoswitchable ligands targeting β-ARs and yielded four key compounds (photo-clenbuterol, opto-prop-2, (S)-opto-prop-2 and (S)-opto-prop-2-vis) to optically modulate β2-AR signaling with spatiotemporal precision. Multiple GPCR assays are used to characterize their pharmacological properties in vitro and in vivo, such as radioligand binding assays, FRET-based cAMP generation assays, and rabbit ocular hypertension measurements. Finally, we concluded that these photoswitchable ligands allow precise control of β2-AR signaling at the level of cells, tissue, or pathophysiological processes. The above photoswitchable ligands offer key insights into photopharmacology and might hold promise for β2-AR-targeted therapies using light to reduce on-target side effects.