Optical control of dopamine receptors in vitro and in vivo with photoswitchable ligands

(Flash Poster Presentation F18) Understanding the dopaminergic system dynamics is a central question in neurobiology and neuropharmacology. Dopamine receptors are involved in the modulation of fundamental physiological functions, including voluntary movement, feeding, reward, motivation, sleep, attention, memory, and cognition, and a dysregulation of the dopaminergic transmission is generally associated with severe neurological disorders. However, the available techniques to dissect neuronal circuits and their role in pathological conditions have several drawbacks. Light is an unparalleled input signal to noninvasively manipulate biological systems with high spatiotemporal precision, and photopharmacology, that relies on the use of molecular photoswitches to regulate the activity of bioactive compounds, has already proved to be a successful approach. We present here a set of novel photoswitchable ligands, named azodopas, that allow reversible spatiotemporal control of dopaminergic transmission. Azodopas enable reversibly photocontrolling zebrafish motility on a time scale of seconds. Moreover, azodopa-1 increases the overall neural activity in the cortex of anesthetized mice and displays light-dependent activity in individual cells. Azodopas are the first photoswitchable dopamine agonists with demonstrated efficacy in wildtype animals and open the way to remotely controlling dopaminergic neurotransmission for fundamental and therapeutic purposes. References Matera C, et al. ChemRxiv 2022. DOI: 10.26434/chemrxiv-2022-8jlxp.