Positive allosteric modulators of metabotropic glutamate 1 receptor: Characterization, mechanism of action, and binding site

We have identified two chemical series of compounds acting as selective pos itive allosteric modulators (enhancers) of native and recombinant metabotro pic glutamate 1 (mGlu1) receptors. These compounds did not directly activat e mGlu1 receptors but markedly potentiated agonist-stimulated responses, in creasing potency and maximum efficacy. Binding of these compounds increased the affinity of a radiolabeled glutamate-site agonist at its extracellular N-terminal binding site. Chimeric and mutated receptors were used to local ize amino acids in the receptor transmembrane region critical for these enh ancing properties. Finally, the compounds potentiated synaptically evoked r i receptor responses in rat brain slices. The discovery of selective positi ve allosteric modulators of mGlu1 receptors opens up the possibility to dev elop a similar class of compounds for other family 3 G protein-coupled rece ptors.