Cannabinoid receptor 2 (CB2) is a promising target for the treatment of neuroinflammation and other diseases. Howev-er, lack of understanding of its complex signaling in cells and tissues complicates its therapeutic targeting. For the first time we show that HU308 increases cytosolic Ca<sup>2+</sup> levels in mammalian cells via CB2 and phospholipase C. We report the synthesis of pho-toswitchable derivatives of CB2 agonist HU308, azo-HU308s, from central building block 3-OTf-HU308. Azo-HU308s enable optical control over CB2 activity with spatiotemporal precision, as demonstrated in real-time Ca<sup>2+</sup> fluorescence imaging. Our findings reveal a novel messenger pathway by which HU308 and its derivatives can affect cellular excitability, and demonstrate the utility of chemical photoswitches to control CB2 signaling in real time.
Optical Control of Cannabinoid Receptor 2-Mediated Ca2+ Release Enabled by Synthesis of Photoswitchable Probes
