Optogluram-2: a subtype-selective photoswitchable positive allosteric modulator for metabotropic glutamate receptor 4

Background and Purpose Metabotropic Glutamate Receptors (mGlu) regulate multiple functions in the nervous systems and are involved in multiple 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, which is a positive allosteric modulator (PAM) of mGlu4 that enables to optically control physiological responses with a high precision. However, Optogluram is not fully selective and finding mGlu4 PAMs with subtype selectivity may be complicated. Experimental Approach New photoswitchable analogues of Optogluram were synthesised with the aim of obtaining photoswitchable PAMs selective for mGlu4 receptor and with improved photoisomerization properties. The photopharmacological profiles of these new compounds were assessed using spectroscopy, functional IP and cAMP assays and computational modelling. Key Results Optogluram-2 emerged as a new photoswitchable PAM for mGlu4 receptor and offered improved photoswitching properties and was selective for mGlu4. Optogluram-2 had activity as both PAM and allosteric agonist. The π-π stacking of the thiazole ring in the allosteric pocket of mGlu6 is hypothesised to be responsible of the mGlu4 selectivity. Conclusion and Implications. The enhanced photoswitching behaviour and improved selectivity of Optogluram-2 makes it an excellent candidate to study the role of mGlu4 with a high spatiotemporal precision that only photopharmacology can offer. Indeed, the use of Optogluram-2 in tissues where mGlu4 can be co-expressed with other mGlu receptors will help to unravel the complexity of mGlu receptors in neural transmission, pinpointing the role of mGlu4 in such systems.