Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003-CiM), Westfälische Wilhelms-Universität Münster, Germany.
Institut für Pharmazeutische und Medizinische Chemie der Universität Münster, Corrensstraße 48, D-48149 Münster, Germany.
Eur J Med Chem. 2018 Jan 20;144:672-681. doi: 10.1016/j.ejmech.2017.12.054. Epub 2017 Dec 18.
Antagonists addressing selectively NMDA receptors containing the GluN2B subunit are of particular interest for the treatment of various neurological disorders including neurodegenerative diseases. With the aim to bioisosterically replace the metabolically labile phenol of 7-amino-6,7,8,9-tetrahydro-5H-benzo[7]annulen-2-ols, several analogs were docked into the ifenprodil binding site leading to the hydroxymethyl derivatives 4 as promising candidates. They display the same binding pose as Ro 25-6981 and the same H-bond interactions with Gln110 and Glu236 within the GluN2B subunit. The phenylalkyl moieties occupy the hydrophobic pocket formed predominantly by Pro78 (GluN2B), Phe114 (GluN2B), and Tyr109 (GluN1b). Starting from o-phthalaldehyde, the hydroxymethyl derivatives 4 were prepared in a 7-step synthesis with a haloform reaction of trichloroacetophenone 7 as key step. In receptor binding studies, the phenylpropyl derivative 4a shows promising GluN2B affinity (K = 101 nM) and high selectivity over the PCP binding site and both σ receptor subtypes. 4a was able to inhibit the glutamate/glycine induced cytotoxicity at mouse fibroblasts with an IC value of 5.2 μM. It is assumed that the hydroxymethyl moiety of 4a stabilizes the closed channel conformation by an H-bond with Glu236 as does the phenolic OH moiety of 3, Ro 25-6981 and ifenprodil.
选择性作用于包含 GluN2B 亚基的 NMDA 受体的拮抗剂特别适合治疗各种神经紊乱，包括神经退行性疾病。为了生物等排取代 7-氨基-6,7,8,9-四氢-5H-苯并[7]环庚烯-2-醇中代谢不稳定的酚，将几种类似物对接进入ifenprodil 结合位点，得到了具有前景的羟甲基衍生物 4。它们与 Ro 25-6981 具有相同的结合构象，与 GluN2B 亚基中的 Gln110 和 Glu236 具有相同的氢键相互作用。苯烷基部分占据由 Pro78 (GluN2B)、Phe114 (GluN2B)和 Tyr109 (GluN1b) 主要形成的疏水性口袋。以邻苯二醛为起始原料，通过三氯乙酮 7 的卤仿反应作为关键步骤，经 7 步合成得到了羟甲基衍生物 4。在受体结合研究中，苯基丙基衍生物 4a 表现出良好的 GluN2B 亲和力（K = 101 nM），对 PCP 结合位点和两种 σ 受体亚型具有高选择性。4a 能够抑制谷氨酸/甘氨酸诱导的小鼠成纤维细胞细胞毒性，IC 值为 5.2 µM。假设 4a 的羟甲基部分通过与 Glu236 的氢键稳定了闭合通道构象，就像 3、Ro 25-6981 和 ifenprodil 的酚羟基部分一样。
