Novel 3-carboxy-and 3-phosphonopyrazoline amino acids as potent and selective NMDA receptor antagonists: Design, synthesis, and pharmacological characterization

The design and synthesis of new N1-substituted 3-carboxyand 3-phosphonopyrazoline and pyrazole amino acids that target the glutamate binding site of NMDA receptors are described. An analysis of the stereochemical requirements for high-affinity interaction with these receptors was performed. We identified two highly potent and selective competitive NMDA receptor antagonists, (5S,αR)-1 and (5S,αR)-4, which exhibit good in vitro neuroprotective activity and in vivo anticonvulsant activity by i.p. administration, suggesting that these molecules may have potential use as therapeutic agents.