In vitro pharmacological evaluation of a photoswitchable modulator in dopaminergic receptors

Dopamine is a key neurotransmitter involved in essential physiological and neurological processes including motor control, learning, motivation, and cognition. Dysregulation of dopaminergic signaling may arise due to neuronal degeneration, receptor malfunction, or diseases. Current treatment for these disorders relies on pharmacological dopamine agonists to modulate dopaminergic receptors and transmission. However, these conventional agonist often produce significant side effects due to their limited receptor and saptiotemporal specificity. To overcome these limtiations, BRJ-1 was developed as a reversible photopharmacological agonist designed to obtain a spatiotemporal modulation of dopaminergic receptors. To characterize its photopharmacological properties, we performed real-time calcium imaging assays in transiently transfected HEK-tsA201 cells under different illumination conditions. Cells were transfected with D1and D2 receptors, a calcium sensor, and specific chimeric/promiscuous proteins needed for intracellular calcium release. We demonstrated that BRJ-1 activates D1 receptors in its trans configuration and this effect can be abolished upon illumation at 380 nm, which switches the molecule into the cis form. Thus, BRJ-1 enables a reversible photocontrol of D1R. These results highlight a potential of BRJ1 as a tool for therapeutic approaches requiring selective spatiotemporal modulation of this receptor subtype or for future research studies to establish how dopaminergic neurotransmission governs neuronal circuits and its influence on physiological processes.