To investigate the structural requirements for selective activation or blockade of metabotropic glutamate receptors, we developed a pharmacophore model for group I (mGluR1) and group II (mGluR2) agonists. The Apex-3D program was used with a training set of known active, inactive, and/or selective compounds with a wide structural diversity. The pharmacophore models were then validated by testing a set of additional known agonists. We also used competitive antagonist superpositions in order to define more precisely the topology of the mGluR1 and mGluR2 agonists' recognition site. Both models account for the activity of most potent compounds and show that the selectivity between mGluR1 and mGluR2 subtypes may be due to excluded volumes and additional binding sites, while the relative spatial position of functional groups (NH2, alpha- and gamma-CO2H) remains very similar. On both models glutamate lies in an extended form. An additional binding site is disclosed on mGluR1, while this region would be forbidden on mGluR2. This new site combines a closed and an open model for mGluR1 and accounts for the increased affinity of quisqualic acid. The models show another large hydrophobic region which is tolerated for mGluR2 and restricted for mGluR1.