Potent Quinoxaline-Spaced Phosphono α-Amino Acids of the AP-6 Type as Competitive NMDA Antagonists: Synthesis and Biological Evaluation

Article abstract of DOI:10.1021/jm00055a004

A series of α-amino-3-(phosphonoalkyl)-2-quinoxalinepropanoic acids was synthesized and evaluated for NMDA receptor affinity using a <3H>CPP binding assay.Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated <3H>TCP binding assay and in vivo by empolying an NMDA-induced seizure model.Some analogues also were evaluated in the <3H>-glycine binding assay.Several compounds of the AP-6 type show potent and selective NMDA antagonistic activity both in vitro and in vivo.In particular α-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) d isplayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model.Noteworthy is α-amino-6,7-dichloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (3) with a unique dual activity, displaying in the NMDA receptor binding assay an IC50 of 3.4 nM and in the glycine binding assay an IC50 of 0.61 μM.