Amino-pyrrolidine tricarboxylic acids give new insight into group III metabotropic glutamate receptor activation mechanism. Mol Pharmacol 71:704–712

Like most class C G-protein-coupled receptors, metabotropic glutamate (mGlu) receptors possess a large extracellular do-main where orthosteric ligands bind. Crystal structures re-vealed that this domain, called Venus FlyTrap (VFT), adopts a closed or open conformation upon agonist or antagonist bind-ing, respectively. We have described amino-pyrrolidine tricar-boxylic acids (APTCs), including (2S,4S)-4-amino-1-[(E)-3-car-boxyacryloyl]pyrrolidine-2,4-dicarboxylic acid (FP0429), as new selective group III mGlu agonists. Whereas FP0429 is an almost full mGlu4 agonist, it is a weak and partial agonist of the closely related mGlu8 subtype. To get more insight into the activation mechanism of mGlu receptors, we aimed to elucidate why FP0429 behaves differently at these two highly homologous receptors by focusing on two residues within the binding sit