Dirk Trauner (@dirktrauner.bsky.social)

Photoswitchable Diazocine Derivative for Adenosine A3 Receptor Activation in Psoriasis Incorporating photoisomerizable moieties within drugs offers the possibility of rapid and reversible light-dependent switching between active and inactive configurations. Here, we developed a photoswitchable adenosine A3 receptor (A3R) agonist that confers optical control on this G protein-coupled receptor through noninvasive topical skin irradiation in an animal model of psoriasis. This was achieved by covalently bonding an adenosine-5′-methyluronamide moiety to a diazocine photochrome, whose singular photoswitching properties facilitated repeated interconversion between a thermally stable, biologically inactive Z agonist form and a photoinduced, pharmacologically active E configuration. As a result, our photoswitchable agonist allowed the precise modulation of A3R function both in vitro and in vivo, which led to a clear light-controlled pharmacotherapeutic effect on mouse skin lesions. This breakthrough not only demonstrates the potential of diazocine photoswitches for in vivo photopharmacology but also paves the way for the development of new strategies for skin-related diseases that require localized and temporally controlled drug action. https://pubs.acs.org/doi/10.1021/jacs.4c13558