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
Pharmacology Unit, Department of Pathology and Experimental Therapeutics, Faculty of Medicine and Health Sciences, Institute of Neurosciences, University of Barcelona, L'Hospitalet de Llobregat 08907, Spain.
Neuropharmacology and Pain Group, Neuroscience Program, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat 08907, Spain.
J Am Chem Soc. 2025 Jan 8;147(1):874-879. doi: 10.1021/jacs.4c13558. Epub 2024 Dec 16.
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 (AR) 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 AR 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.
在药物中引入可光异构化部分，使得药物有可能在活性和非活性构型之间快速且可逆地进行光控转换。在此，我们开发了一种可光开关的腺苷A受体（AR）激动剂，在银屑病动物模型中，通过非侵入性局部皮肤照射，对这种G蛋白偶联受体进行光学控制。这是通过将腺苷 - 5'-甲基脲酰胺部分共价连接到重氮辛光色素上实现的，其独特的光开关特性促进了热稳定、生物无活性的激动剂形式与光诱导的、药理活性的构型之间的反复相互转换。结果，我们的可光开关激动剂能够在体内和体外精确调节AR功能，这对小鼠皮肤损伤产生了明显的光控药物治疗效果。这一突破不仅证明了重氮辛光开关在光药理学中的潜力，也为开发针对需要局部和时间控制药物作用的皮肤相关疾病的新策略铺平了道路。
