Synthesis of N1-substituted analogues of (2R,4R)-4-amino-pyrrolidine-2,4-dicarboxylic acid as agonists, partial agonists, and antagonists of group II metabotropic glutamate receptors

The chemical synthesis of a series of N1-substituted derivatives of (2R,4R)-4-aminopyrrolidine-2,4-dicarboxylic acid [(2R,4R)-APDC] as constrained analogues of γ-substituted glutamic acids is described. Appropriate substitution of the N1-position results in agonist, partial agonist, or antagonist activity at mGluR2, mGluR3, and/or mGluR6.