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 through the utilization of photoswitchable compounds such as optogluram, which is a positive allosteric modulator (PAM) of mGlu 4 that enables the precise control of physiological responses using light but does not have an optimal selectivity profile. Optogluram analogs were developed to obtain photoswitchable PAMs of mGlu 4 receptor with an improved selectivity. Among them, optogluram-2 emerged as a photoswitchable ligand for mGlu 4 receptor with activity as both PAM and allosteric agonists. It presents a higher selectivity and offers improved photoswitching of mGlu 4 activity. These improved properties make optogluram-2 an excellent candidate to study the role of mGlu 4 with a high spatiotemporal precision in systems where mGlu 4 can be co-expressed with other mGlu receptors.