To determine the eutomers of potent GluN2B‐selective N‐methyl‐d‐aspartate (NMDA) receptor antagonists with a 3‐benzazepine scaffold, 7‐benzyloxy‐3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepin‐1‐ols (S)‐2 and (R)‐2 were separated by chiral HPLC. Hydrogenolysis and subsequent methylation of the enantiomerically pure benzyl ethers of (S)‐2 and (R)‐2 provided the enantiomeric phenols (S)‐3 and (R)‐3 [3‐(4‐phenylbutyl)‐2,3,4,5‐tetrahydro‐1H‐3‐benzazepine‐1,7‐diol] and methyl ethers (S)‐4 and (R)‐4. All enantiomers were obtained with high enantiomeric purity (≥99.7 % ee). The absolute configurations were determined by CD spectroscopy. R‐configured enantiomers turned out to be the eutomers in receptor binding studies and two‐electrode voltage clamp experiments. The most promising ligand of this compound series is the R‐configured phenol (R)‐3, displaying high GluN2B affinity (K_i=30 nm), high inhibition of ion flux (IC₅₀=61 nm), and high cytoprotective activity (IC₅₀=93 nm). Whereas the eudismic ratio in the receptor binding assay is 25, the eudismic ratio in the electrophysiological experiment is 3.

中文翻译：

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对映体纯的GluN2B选择性NMDA受体拮抗剂的合成及药理评价

要确定的强效GluN2B选择性的eutomers Ñ甲基d天冬氨酸（NMDA）与3-苯并氮杂支架受体拮抗剂，7-苄氧基-3-（4-苯基丁基）-2,3,4,5-四氢通过手性HPLC分离了1 H -3-苯并ze庚因-1-醇（S）-2和（R）-2。（S）-2和（R）-2对映体纯苄基醚的氢解和随后的甲基化反应提供了对映体酚（S）-3和（R）-3 [3-（4-苯基丁基）-2,3， 4,5-四氢-1H -3-苯并ze庚因-1,7-二醇]和甲基醚（S）-4和（R）-4。获得的所有对映体均具有较高的对映体纯度（≥99.7％  ee）。绝对构型通过CD光谱法确定。在受体结合研究和两电极电压钳实验中，R-配置的对映异构体被证明是自发体。该化合物系列中最有前途的配体是R构型的苯酚（R）-3，显示出高的GluN2B亲和力（K _i = 30 n m），对离子通量的高抑制作用（IC ₅₀ = 61 n m）和高的细胞保护活性（IC ₅₀ = 93 n m）。受体结合测定中的eudismic比率为25，而电生理实验中的eudismic比率为3。