Photoswitchable Diazocine Derivative for Adenosine A₃ Receptor Activation in Psoriasis

Abstract

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 <i>Z</i> agonist form and a photoinduced, pharmacologically active <i>E</i> configuration. As a result, our photoswitchable agonist allowed the precise modulation of A₃R function both <i>in vitro</i> and <i>in vivo</i>, which led to a clear light-controlled pharmacotherapeutic effect on mouse skin lesions. This breakthrough not only demonstrates the potential of diazocine photoswitches for <i>in vivo</i> photopharmacology but also paves the way for the development of new strategies for skin-related diseases that require localized and temporally controlled drug action.