Potent quinoxaline-spaced phosphono alpha-amino acids of the AP-6 type as competitive NMDA antagonists: synthesis and biological evaluation |
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Authors: | RB Baudy LP Greenblatt IL Jirkovsky M Conklin RJ Russo DR Bramlett TA Emrey JT Simmonds DM Kowal RP Stein |
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Affiliation: | Division of CNS Chemistry, Wyeth-Ayerst Research Inc, Princeton, New Jersey 08543-8000. |
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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. |
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