title: Potent quinoxaline-spaced phosphono alpha-amino acids of the AP-6 type as competitive NMDA antagonists: synthesis and biological evaluation.
abstract: 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.
authors.affiliation: Division of CNS Chemistry, Wyeth-Ayerst Research Inc, Princeton, New Jersey 08543-8000.
authors.forename: R B
authors.initials: RB
authors.lastname: Baudy
authors.forename: L P
authors.initials: LP
authors.lastname: Greenblatt
authors.forename: I L
authors.initials: IL
authors.lastname: Jirkovsky
authors.forename: M
authors.initials: M
authors.lastname: Conklin
authors.forename: R J
authors.initials: RJ
authors.lastname: Russo
authors.forename: D R
authors.initials: DR
authors.lastname: Bramlett
authors.forename: T A
authors.initials: TA
authors.lastname: Emrey
authors.forename: J T
authors.initials: JT
authors.lastname: Simmonds
authors.forename: D M
authors.initials: DM
authors.lastname: Kowal
authors.forename: R P
authors.initials: RP
authors.lastname: Stein
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D016202:N-Methylaspartate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D011810:Quinoxalines / Q000138:chemical synthesis / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism
chemical_list: D011810:Quinoxalines; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D015763:2-Amino-5-phosphonovalerate