Synthesis and biological evaluation of (2S)- and (2R)-2-(3′-phosphonobicyclo[1.1.1]pentyl)glycines as novel group III selective metabotropic glutamate receptor ligands

The synthesis of (2S)- and (2R)-2-(3′-phosphonobicyclo[1.1.1]pentyl)glycine isomers (10 and 11), characterized by the bioisosteric replacement of the distal carboxylic group of 2-(3′-carboxybicyclo[1.1.1]pent-1-yl)glycine by the phosphonate moiety, was accomplished by a stereoselective Ugi condensation. The two isomers were tested for their activity against an array of metabotropic glutamate receptors, and the S-isomer (10) turned out to be a moderately potent and selective mGluR4 agonist.