Agonist selectivity of mGluR1 and mGluR2 metabotropic receptors: A different environment but similar recognition of an extended glutamate conformation

To investigate the structural requirements for selective activation or bloc kade of metabotropic glutamate receptors, we developed a pharmacophore mode l 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 co mpounds with a wide structural diversity. The pharmacophore models were the n validated by testing a set of additional known agonists. We also used com petitive antagonist superpositions in order to define more precisely the to pology of the mGluR1 and mGluR2 agonists' recognition site. Both models acc ount for the activity of most potent compounds and show that the selectivit y between mGluR1 and mGluR2 subtypes may be due to excluded volumes and add itional binding sites, while the relative spatial position of functional gr oups (NH2, alpha- and gamma-CO2H) remains very similar. On both models glut amate lies in an extended form. An additional binding site is disclosed on mGluR1, while this region would be forbidden on mGluR2. This new site combi nes a closed and an open model for mGluR1 and accounts for the increased af finity of quisqualic acid. The models show another large hydrophobic region which is tolerated for mGluR2 and restricted for mGluR1.