Laboratorium für Organische Chemie, Eidgenössische Technische Hochschule Zürich, Vladimir-Prelog-Weg 3, 8093 Zürich, Switzerland.
Vollum Institute, Oregon Health & Science University, 3181 SW Sam Jackson Park Road, Portland, Oregon 97239-3098, United States.
J Am Chem Soc. 2021 Jan 20;143(2):736-743. doi: 10.1021/jacs.0c08926. Epub 2021 Jan 5.
Cannabinoid receptor 2 (CB2) is a promising target for the treatment of neuroinflammation and other diseases. However, a lack of understanding of its complex signaling in cells and tissues complicates the therapeutic exploitation of CB2 as a drug target. We show for the first time that benchmark CB2 agonist HU308 increases cytosolic Ca levels in AtT-20(CB2) cells via CB2 and phospholipase C. The synthesis of photoswitchable derivatives of HU308 from the common building block enables optical control over this pathway with spatiotemporal precision, as demonstrated in a real-time Ca fluorescence assay. Our findings reveal a novel messenger pathway by which HU308 and its derivatives affect cellular excitability, and they demonstrate the utility of chemical photoswitches to control and monitor CB2 signaling in real-time.
大麻素受体 2（CB2）是治疗神经炎症和其他疾病的有希望的靶点。然而，由于对其在细胞和组织中的复杂信号传导缺乏了解，使得将 CB2 作为药物靶点进行治疗性开发变得复杂。我们首次表明，基准 CB2 激动剂 HU308 通过 CB2 和磷脂酶 C 增加 AtT-20（CB2）细胞中的细胞溶质 Ca 水平。从常见的构建块合成 HU308 的光致变色衍生物使通过时空精度对该途径进行光学控制成为可能，如实时 Ca 荧光测定中所示。我们的发现揭示了 HU308 及其衍生物影响细胞兴奋性的新信使途径，并证明了化学光开关在实时控制和监测 CB2 信号传导方面的实用性。
