Optogenetic approaches are viewed as very promising approaches to tackle physiological processes, and eventually for space and time-controlled therapeutic interventions. However, the need for transgenes has limited the development of these approaches. An alternative consists of using light-activable compounds that can reach their target only upon light activation, and thus allowing the regulation of GPCR activity in space and time.
Thus, photopharmacology is a new discipline that allows a temporal and spatial remote control of ligand activity, since drugs are locally activated in the target tissue. Interestingly, we recently developed several photosensitive drugs for GPCRs, including a negative allosteric modulator of the metabotropic glutamate type 5 receptor, which elicited analgesic effects upon peripheral and central irradiation (Font et al., 2017), and an adenosine A2A receptor antagonist which promoted locomotor activity in an animal models of parkinsonisms (Taura et al., 2018). Based on this experience, we aim to expand the design, synthesizes, and characterization of GPCRs ligands allowing the local light-dependent receptor modulation, thus minimizing the appearance of side-effects. Indeed, we managed to photodeliver morphine to the spinal cord by means of flexible fibre-optics (López-Cano et al., 2021), which could represent a highly translational strategy.
Additional reading:
Photomodulation of G protein-coupled adenosine receptors by a novel light-switchable ligand.(2014) Bahamonde, M.I.*, Taura, J.*, Paoletta, S.*, Gakh, A.A., Chakraborty, S., Hernando, J., Fernández-Dueñas, V., Jacobson, K.A., Gorostiza, P. & Ciruela, F. Bioconjugate Chemistry 25 (10), 1847-1854.
Optical control of pain in vivo with a photoactive mGlu5 receptor negative allosteric modulator. (2017) Font, J., López-Cano, M., Notartomaso, S., Scarselli, P., Di Prieto, P., Bresolí-Obach, R., Battaglia, G., Malhaire, F., Rovira, X., Catena, J., Giraldo, J., Pin, J.P., Fernández-Dueñas, V., Goudet, C., Nonell, S., Nicoletti, F., Llebaria, A., Ciruela, F. eLife 6, e23545.
Remote control of movement disorders using a photoactive adenosine A 2A receptor antagonist. (2018) Taura, J., Nolen E.G., Cabré, G., Hernando, J., Squarcialupi, L., López-Cano, M., Jacobson, K.A., Fernández-Dueñas, V. & Ciruela, F. Journal of Controlled Release 283, 135-142.