Metabotropic glutamate receptors (mGlu) are class C G protein-coupled receptors of
eight subtypes that are omnipresently expressed in the central nervous system. mGlus
have relevance in several psychiatric and neurological disorders, therefore they raise
considerable interest as drug targets. Allosteric modulators of mGlus offer advantages
over orthosteric ligands owing to their increased potential to achieve subtype selectivity,
and this has prompted discovery programs that have produced a large number of reported
allosteric mGlu ligands. However, the optimization of allosteric ligands into drug
candidates has proved to be challenging owing to induced-fit effects, flat or steep
structure-activity relationships and unexpected changes in theirpharmacology. Subtle
structural changes identified as molecular switches might modulate the functional
activity of allosteric ligands. Here we review these switches discovered in the metabotropic
glutamate receptor family..