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 mGlu₄ 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 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 agonists. 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.

Biochemistry; biological sciences; molecular biology; natural sciences; pharmacology.