Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074, Würzburg, Germany.
Institut für Pharmakologie und Toxikologie, Julius-Maximilians-Universität Würzburg, Versbacher Str. 9, 97078, Würzburg, Germany.
Angew Chem Int Ed Engl. 2023 Dec 4;62(49):e202306176. doi: 10.1002/anie.202306176. Epub 2023 Jul 13.
The cannabinoid 2 receptor (CB R) has high therapeutic potential for multiple pathogenic processes, such as neuroinflammation. Pathway-selective ligands are needed to overcome the lack of clinical success and to elucidate correlations between pathways and their respective therapeutic effects. Herein, we report the design and synthesis of a photoswitchable scaffold based on the privileged structure of benzimidazole and its application as a functionally selective CB R "efficacy-switch". Benzimidazole azo-arenes offer huge potential for the broad extension of photopharmacology to a wide range of optically addressable biological targets. We used this scaffold to develop compound 10 d, a "trans-on" agonist, which serves as a molecular probe to study the β-arrestin2 (βarr2) pathway at CB R. βΑrr2 bias was observed in CB R internalization and βarr2 recruitment, while no activation occurred when looking at Gα or mini-Gα . Overall, compound 10 d is the first light-dependent functionally selective agonist to investigate the complex mechanisms of CB R-βarr2 dependent endocytosis.
大麻素 2 型受体（CB R）在多种致病过程中具有很高的治疗潜力，如神经炎症。需要途径选择性配体来克服临床应用的不足，并阐明途径与其各自治疗效果之间的相关性。本文报告了基于苯并咪唑特权结构的光致开关支架的设计和合成，并将其用作功能选择性 CB R“效价开关”。苯并咪唑偶氮芳烃为将光药理学广泛扩展到广泛的光可寻址生物靶标提供了巨大的潜力。我们使用该支架开发了化合物 10d，一种“顺式开启”激动剂，作为研究 CB R 中β-arrestin2（βarr2）途径的分子探针。在 CB R 内化和 βarr2 募集过程中观察到 βΑrr2 偏向，而在观察 Gα 或 mini-Gα 时则没有发生激活。总的来说，化合物 10d 是第一个用于研究 CB R-βarr2 依赖性内吞作用的复杂机制的光依赖性功能选择性激动剂。
