Photoswitchable positive allosteric modulators of metabotropic glutamate receptor 4 to improve selectivity

Metabotropic Glutamate Receptors (mGlu) regulate multiple functions in the nervous systems and are involved in several neurological disorders. However, selectively targeting individual mGlu subtypes with spatiotemporal precision is still an unmet need. Photopharmacology can address this concern by means of photoswitchable compounds such as Optogluram is a positive allosteric modulator (PAM) of mGlu4 that enables the control of physiological responses with a high precision using light but has not an optimal selectivity profile. Optogluram analogs were developed to obtain photoswitchable PAMs of mGlu4 receptor with an improved selectivity. Among them, Optogluram-2 emerged as a photoswitchable ligand for mGlu4 receptor with activity as both PAM and allosteric agonist. It presents a higher selectivity and offers improved photoswitching of mGlu4 activity. These improved properties make Optogluram-2 an excellent candidate to study the role of mGlu4 with a high spatiotemporal precision in systems where mGlu4 can be co-expressed with other mGlu receptors.