Photo-clenbuterol: Optical Control of β2‑Adrenergic Receptor Signaling by Photoswitchable Ligand Efficacy

Clenbuterol is a potent partial agonist on the human β2-adrenergic receptor (β2-AR) and available for veterinary use to treat respiratory diseases. We executed an “azoextension” strategy to generate a small library of photoresponsive azobenzene derivatives of clenbuterol. Illumination with two complementary wavelengths allowed interconversion between isomeric trans and cis forms, as proven by UV/vis, NMR and LC–MS studies. The photoswitchable clenbuterol analogs were pharmacologically characterized using β2-AR radioligand binding and cAMP assays. Key compound 12b (VUF26034) has suitable photochemical properties and good thermal stability of the cis isomer (t1/2 ∼ 4 months), switching from a partial agonist to a >25-fold higher affinity antagonist upon illumination with 360 nm.