Photocaging of a GPR52 agonist enables light-dependent receptor activation in cells.

GPR52 is an orphan G protein-coupled receptor implicated in neuropsychiatric disorders and has attracted interest as a small-molecule drug discovery target. Here, we report the design, synthesis, and biological evaluation of photocaged derivatives of the GPR52 agonist 7d. Among the derivatives prepared, DMNB-7d showed markedly reduced basal activity in the dark and underwent photoactivation under 405 nm irradiation. In a GPR52 Tango/HTLA cell-based assay, direct irradiation of DMNB-7d-treated cells restored receptor activation, demonstrating light-dependent control of GPR52 signaling in a cellular context. Pre-irradiated DMNB-7d also showed a behavioral pharmacological effect consistent with that of the parent agonist in an MK-801-induced hyperlocomotion assay. These results identify DMNB-7d as a photoactivatable GPR52 agonist and provide a proof-of-concept strategy for developing light-responsive ligands targeting GPR52.