GRM5 and major depressive disorder: Potent NAMsand PAMs of several subtypes have been identified, and mGlu5 modulators (Figure 2) have reached clinical trials for different indications (e.g. fragileX syndrome, depression, and Parkinson’s disease).18 Crystal structures of mGlu5 alsorevealed that NAMs bind to an intrahelical pocket in the 7TM regionand provide opportunities to design novel allosteric modulators usingstructure-based modeling.8,9,17,19,20