The NMDA receptor containing GluN2B subunits represents a promising target for the development of drugs for the treatment of various neurological disorders including neurodegenerative diseases. In order to study the role of CH₃ and OH moieties trisubstituted tetrahydro-3-benzazepines 4 were designed as missing link between tetra- and disubstituted 3-benzazepines 2 and 5. The synthesis of 4 comprises eight reaction steps starting from alanine. The intramolecular Friedel-Crafts acylation to obtain the ketone 12 and the base-catalyzed elimination of trifluoromethanesulfinate (CF₃SO₂⁻) followed by NaBH₄ reduction represent the key steps. The GluN2B affinity of the cis-configured 3-benzazepin-1-ol cis-4a with a 4-phenylbutyl side chain (K_i = 252 nM) is considerably lower than the GluN2B affinity of (R,R)-2 (K_i = 17 nM) indicating the importance of the phenolic OH moiety for the interaction with the receptor protein. Introduction of an additional CH₃ moiety in 2-position led to a slight decrease of GluN2B affinity as can be seen by comparing the affinity data of cis-4a and 5. The homologous phenylpentyl derivative cis-4b shows the highest GluN2B affinity (K_i = 56 nM) of this series of compounds. According to docking studies cis-4a adopts the same binding mode as the cocrystallized ligand ifenprodil-keto 1A and 5 at the interface of the GluN2B and GluN1a subunits. The same crucial H-bonds are formed between the C(O)NH₂ moiety of Gln110 within the GluN2B subunit and the protonated amino moiety and the OH moiety of (R,R)-cis-4a.

含有GluN2B亚基的NMDA受体代表了开发用于治疗包括神经退行性疾病在内的各种神经系统疾病的药物的有希望的目标。为了研究CH ₃和OH部分的作用，将三取代四氢-3-苯并ze庚因4设计为四和二取代3-苯并ze庚因2和5之间的缺失连接。4的合成包括从丙氨酸开始的八个反应步骤。分子内Friedel-Crafts酰化，得到酮12和碱催化的消除三氟甲基亚磺酸（CF ₃ SO ₂ ^- ），随后加入NaBH ₄减少是关键步骤。所述的GluN2B亲和力顺-构型3-苯并吖庚因-1-醇顺-图4a用4-苯丁基侧链（ķ_我 = 252 nm）的比（在GluN2B亲和力显着地降低- [R ，- [R ）- 2（K_我 ＝ 17nM）表明酚OH部分对于与受体蛋白相互作用的重要性。通过比较顺式4a和5的亲和力数据可以看出，在2位引入额外的CH ₃部分导致GluN2B亲和力略有下降。同源苯基戊基衍生物顺式-图4b示出了最高GluN2B亲和力（ķ_我 = 56 nM）的这一系列的化合物。根据对接研究顺- 4a中采用相同的结合模式为共结晶配体艾芬地尔酮1A和5在GluN2B和GluN1a亚基的接口。同样关键的氢键是本C（之间形成O）NH ₂ Gln110的GluN2B亚基内部分和质子化氨基部分和（OH部分- [R ，- [R - ）顺式- 4a中。