The structures are shown for six classes of NMDA receptor antagonists.

Reagents and conditions: (a) LiAlH₄, THF, 0 °C to rt; (b) CDI, THF, rt.

Schematic of the NMDA receptor antagonist pharmacophore (7) compared to an NR2B-selective enantiomeric propanolamine (8) and an NR2B-selective screening hit (9).

Reagents and conditions: (a) LiAlH₄, THF, reflux to rt; (b) pyridine, MsCl, 0 °C to rt; (c) 13, MeOH, reflux.

Reagents and conditions: (a) SOCl₂, MeOH, −10 °C to rt; (b) H₂, 5% Pd/C, MeOH, rt; (c) pyridine, MsCl, 0 °C to rt; (d) 1.0 M NaOH, MeOH, rt.

Reagents and conditions: (a) N-Boc-ethanolamine, PPh₃, DIAD, THF, 0 °C to rt; (b) H₂, 5% Pd/C, MeOH, rt; (c) MsCl, DIPEA, DCM, 0 °C to rt; (d) TFA, DCM, rt; (e) chloroacetyl chloride, Et₃N, DCM, 0 °C to rt; (f) 65, Et₃N THF, reflux.

Reagents and conditions: (a) SOCl₂, MeOH, −10 °C to rt; (b) MsCl, DCM, pyridine, 0 °C to rt; (c) NHNH₂·H₂O, MeOH, reflux; (d) 3,4-dichlorophenylisothiocyanate or 3,4-dichlorophenylisocyanate, DMF, rt; (e) EDCI, 3,4-dichlorophenylacetic acid, DMAP, DMF 0 °C to rt; (f) 3,4-dichlorobenzoic acid, DCC, DMF, 0 °C to rt; (g) 5,6-dichloroisobenzofuran-1,3-dione, DMF, reflux.

Reagents and conditions: (a) bromoethylamine hydrobromide or bromopropylamine HBr, toluene, reflux; (b) N-Boc-aminoethanol, PPh₃, DIAD, THF, 0 °C to rt; (c) TFA, THF, rt; (d) 130 °C; (e) oxalyl choride, THF, DMF, rt; (f) Et₂O, NH₃ in 1,4-dioxane, rt; (g) LiAlH₄, THF, 0 °C to rt; (h) allyl bromide, DMF, 50 °C; (i) 3,4-dichloroiodobenzene (46), Pd(OAc)₂,Et₃N, MeCN, 100 °C; (j) NH₂NH₂·H₂O, EtOH, reflux.

Compound 52 is an NR2B-selective, non-competitive, voltage-independent NMDA receptor inhibitor. (A) Two electrode voltage clamp recordings from Xenopus oocytes were used to measure the mean ± SEM response to glutamate and glycine coapplied with 3 μM compound 52 on various glutamate receptors expressed as a percent of the maximal response evoked by saturating concentrations of agonists (50 μM glutamate plus 30 μM glycine) for the indicated NMDA receptors. Similar experiments were performed on recombinant GluR1 AMPA receptors (100 μM glutamate), and recombinant GluR6 kainate receptors pre-treated with 10 μM concanavalin-A (100 μM glutamate). The effect of 3 μM compound 52 was also evaluated on voltage-dependent sodium and potassium whole cell currents recorded from cultured cortical neurons and elicited by incremental 10 mV step depolarizations from −90 mV to +50 mV. The amplitudes of Na⁺ currents and K⁺ currents in the absence and presence of 3 μM compound 52 were measured at −10 mV and +50 mV, respectively. The numbers in parenthesis are the number of oocytes or neurons tested under each condition. *p <0.05, paired-t-test. (B) Concentration–effect curves for compound 52 were generated in oocytes expressing wild type and mutant NR1/NR2B receptors. The IC₅₀ values of compound 52 were 0.057 μM on rat wild type receptors (n = 18), 52 μM on mouse amino terminal domain D101A point mutants (n = 4) and 563 μM on rat amino terminal domain deletion mutants (n = 3). (C) Increasing the concentration of glutamate does not surmount the inhibition by 0.054 μM of compound 52 (n = 4), suggesting compound 52 inhibits the receptor by a non-competitive mechanism. The mean ± SEM response as a percent control is summarized for experiments raising either glutamate or glycine concentration in the right panel. (D) Inhibition by compound 52 is independent of membrane potential. A representative recording from an oocyte expressing rat NR1/NR2B shows the current–voltage relationship for responses evoked by of 50 μM glutamate plus 30 μM glycine as closed circles and 0.054 μM compound 52 coapplied with 50 μM glutamate plus 30 μM glycine as open circles (representative of eight experiments).