Photoswitchable Diazocine Derivative for Adenosine A 3 Receptor Activation in Psoriasis

• Published in: Journal of the American Chemical Society 2025-01, Vol.147 (1), p.874-879
• Main Authors: López-Cano, Marc, Scortichini, Mirko, Tosh, Dilip K, Salmaso, Veronica, Ko, Tongil, Salort, Glòria, Filgaira, Ingrid, Soler, Concepció, Trauner, Dirk, Hernando, Jordi, Jacobson, Kenneth A, Ciruela, Francisco
• Format: Article
• Language: English
• Subjects: Adenosine A3 Receptor Agonists - chemistry; Adenosine A3 Receptor Agonists - pharmacology; Animals; Humans; Mice; Molecular Structure; Photochemical Processes; Psoriasis - drug therapy; Psoriasis - metabolism; Receptor, Adenosine A3 - metabolism
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/jacs.4c13558

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 A receptor (A R) 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 agonist form and a photoinduced, pharmacologically active configuration. As a result, our photoswitchable agonist allowed the precise modulation of A R function both and , which led to a clear light-controlled pharmacotherapeutic effect on mouse skin lesions. This breakthrough not only demonstrates the potential of diazocine photoswitches for photopharmacology but also paves the way for the development of new strategies for skin-related diseases that require localized and temporally controlled drug action.