Synthesis and NMD A Antagonistic Properties of the Enantiomers of 4-(3-phosphonopropyl)piperazine-2-carboxylic acid (CPP) and of the unsaturated analogue (E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (CPP-ene)

The (R)- and (s)-enantiomers of 4-(3-phosphonopropyl)piperazine-2-carboxylic acid (D - and L -CPP, resp.; 15 and 16 , resp.), and of its unsaturated analogue (E)-4-(3-phosphonoprop-2-enyl)piperazine-2-carboxylic acid (D - and L -CPP-ene, resp.; 13 and 14 , resp.) were prepared. The absolute configuration of the enantiomers was determined by a chemical correlation of the menthyl ester 7 with D -asparagine. The affinity of these derivatives for the NMDA receptor was determined by displacement of [³H]CPP in rat cerebral cortical membranes. In two functional tests (the frog hemisected spinal cord preparation and the sodium efflux test from rat brain slices), D -CPP-ene appears to be the most potent, enantiomerically pure, competitive NMDA antagonist known to date.