Photo-clenbuterol: Optical Control of β<sub>2</sub>-Adrenergic Receptor Signaling by Photoswitchable Ligand Efficacy
Yangzhi Cao, Shuang Shi, Simone A. H. Does, Christian M. L. Buzink, Meichun Gao, Iwan J. P. de Esch, Henry F. Vischer, Maikel Wijtmans, Rob Leurs
Abstract
High Resolution Image Download MS PowerPoint Slide Clenbuterol is a potent partial agonist on the human β 2 -adrenergic receptor (β 2 -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 β 2 -AR radioligand binding and cAMP assays. Key compound 12b (VUF26034) has suitable photochemical properties and good thermal stability of the cis isomer ( t 1/2 ∼ 4 months), switching from a partial agonist to a >25-fold higher affinity antagonist upon illumination with 360 nm.