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NEUROPHARMACOLOGY

Characterization of Two Novel N-Methyl-D-aspartate Antagonists: EAA-090 (2-[8,9-Dioxo-2,6-diazabicyclo [5.2.0]non-1(7)-en2-yl]ethylphosphonic Acid) and EAB-318 (R--Amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic Acid Hydrochloride)

Discovery Neuroscience (L.S., D.C., D.K., R.S., M.S., S.L.) and Chemical Sciences (R.B.), Wyeth Research, Princeton, New Jersey; Department of Neuroscience (R.S.Z.), Albert Einstein College of Medicine, Bronx, New York; and Departments of Psychiatry and Neuropathology (J.O.), Washington University School of Medicine, St. Louis, Missouri

Two novel N-methyl-D-aspartate (NMDA) antagonists with unique chemical structures, EAA-090 (2-[8,9-dioxo-2, 6-diazabicyclo[5.2.0]non-1(7)-en2-yl]ethylphosphonic acid) and EAB-318 (R--amino-5-chloro-1-(phosphonomethyl)-1H-benzimidazole-2-propanoic acid hydrochloride), were compared with CGS-19755 (Selfotel) in ligand binding, electrophysiology, and neuroprotection assays. CGS-19755, EAA-090 and EAB-318 inhibited [³H]3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid binding to NMDA receptors with IC₅₀ values of 55, 28, and 7.9 nM, respectively. All three compounds decreased the duration of spontaneous synaptic currents and inhibited NMDA-activated currents in rat hippocampal neurons. IC₅₀ values for inhibition of current induced by 10 µM NMDA were 795, 477, and 69 nM for CGS-19755, EAA-090, and EAB-318, respectively. The NMDA antagonists protected chick embryo retina slices and cultured rat hippocampal and cortical neurons from glutamate- and NMDA-induced neurotoxicity. In experiments in which different NMDA receptor splice variants and subtypes were expressed in Xenopus oocytes, all three antagonists preferentially blocked NMDA-elicited currents mediated by N-methyl-D-aspartate receptor (NR)1 splice variants containing the N-terminal insertion. They also favored NR2A-versus NR2B- or NR2C-containing NMDA receptors, with EAA-090 showing the greatest selectivity. EAA-090 was 10 times more potent at blocking NR2A-versus NR2B- or NR2C-containing NMDA receptors. In addition to being the most potent NMDA antagonist, EAB-318 inhibited -amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate receptors. The combination of NMDA and AMPA/kainate block enabled EAB-318 to protect neurons against ischemia induced cell death.

Address correspondence to: Dr. Stephen Lin, Discovery Neuroscience, Wyeth Research, CN8000, Princeton, NJ 08543. E-mail: lins{at}wyeth.com

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