Discovery of novel tryptamine derivatives as GluN2B subunit-containing NMDA receptor antagonists via pharmacophore-merging strategy with orally available therapeutic effect of cerebral ischemia
Discovery of novel tryptamine derivatives as GluN2B subunit-containing NMDA receptor antagonists via pharmacophore-merging strategy with orally available therapeutic effect of cerebral ischemia
复制标题
DOI：
10.1016/j.ejmech.2023.115318
复制
发表时间：
2023-04-08
影响因子：
6.7
通讯作者：
Cheng，Maosheng
中科院分区：
文献类型：
--
作者：
Quan，Jishun;Yang，Huali;Cheng，Maosheng
已设计并合成了一系列色胺衍生物作为新型含GluN 2B亚基的NMDA受体（GluN 2B-NMDAR）拮抗剂，其可同时显示代表性GluN 2B-NMDAR拮抗剂ifenprodil（1）和EVT-101（3）的受体-配体相互作用。在本研究中，通过化学合成和药理学表征探索了这些化合物的神经保护潜力。化合物Z25的神经保护活性显著优于阳性对照药物（保护百分比：55.8 ± 0.6%vs.41.0 ± 2.7%），被认为是人GluN 2B-NMDA受体的有效拮抗剂。体外药理学结果表明，Z25可下调NMDA诱导的细胞内Ca ~（2+）浓度升高，上调NMDA诱导的细胞内p-ERK 1/2表达降低，提示Z25是GluN 2B-NMDA受体的拮抗剂。此外，化合物Z25的体外药物样性质的初步评价显示出显著的血浆稳定性。在C57小鼠体内的药代动力学和药效学研究表明，化合物Z25具有较短的半衰期和较低的F值（3.12 ± 0.01%），而给药Z25可显著改善小鼠在一系列脑缺血损伤试验中的认知能力。这些结果支持化合物Z25作为通过拮抗GluN 2B-NMDA受体治疗脑缺血损伤的潜在先导化合物的进一步开发。
A series of tryptamine derivatives has been designed and synthesized as novel GluN2B subunit-containing NMDA receptor (GluN2B-NMDAR) antagonists, which could simultaneously manifest the receptor-ligand interactions of representative GluN2B-NMDAR antagonists ifenprodil (1) and EVT-101 (3). In the present study, the neuroprotective potential of these compounds was explored through chemical synthesis and pharmacological characterization. CompoundZ25with significantly better neuroprotective activity than the positive control drug (percentage of protection: 55.8 ± 0.6%vs.41.0 ± 2.7%) was considered to be an effective antagonist of the human GluN2B-NMDA receptor. Judging fromin vitropharmacological profiling,Z25could downregulate NMDA-induced increased intracellular Ca2+concentration, andZ25could also upregulate NMDA-induced decreased intracellular p-ERK 1/2 expression, which suggested thatZ25is an antagonist of the GluN2B-NMDA receptor. Furthermore, thein vitropreliminary evaluation of the drug-like properties of compoundZ25showed remarkable plasma stability. Based onin vivopharmacokinetic and pharmacodynamic studies in C57 mice, compoundZ25exhibited a relatively short half-life and a low F value (3.12 ± 0.01%), while administration ofZ25substantially improved the cognitive performance of mice in a series of tests of cerebral ischemic injury. Overall, these results support the further development of compoundZ25as a potential lead compound to treat the cerebral ischemic injury by antagonizing GluN2B-NMDA receptor.