Potent quinoxaline-spaced phosphono .alpha.-amino acids of the AP-6 type as competitive NMDA antagonists: synthesis and biological evaluation

• Published in: Journal of medicinal chemistry 1993-02, Vol.36 (3), p.331-342
• Main Authors: Baudy, Reinhardt B, Greenblatt, Lynne P, Jirkovsky, Ivo L, Conklin, Mary, Russo, Ralph J, Bramlett, Donna R, Emrey, Tracy A, Simmonds, Joanne T, Kowal, Dianne M
• Format: Article
• Language: English
• Subjects: 2-Amino-5-phosphonovalerate - analogs & derivatives; 2-Amino-5-phosphonovalerate - chemical synthesis; 2-Amino-5-phosphonovalerate - metabolism; 2-Amino-5-phosphonovalerate - pharmacology; Animals; Binding, Competitive; Brain - metabolism; In Vitro Techniques; Male; Mice; Models, Molecular; Molecular Conformation; N-Methylaspartate - antagonists & inhibitors; N-Methylaspartate - toxicity; Quinoxalines - chemical synthesis; Quinoxalines - pharmacology; Radioligand Assay; Rats; Receptors, N-Methyl-D-Aspartate - metabolism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00055a004

A series of alpha-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 employing 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 alpha-amino-7-chloro-3-(phosphonomethyl)-2-quinoxalinepropanoic acid (1) displayed an ED50 of 1.1 mg/kg ip in the NMDA lethality model. Noteworthy is alpha-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 microM.