类GluN2B选择性NMDA受体对抗剂的昆龙生物异构体
Friederike Rathing1, Dirk Schepmann1, Bernhard Wünsch1,2
1Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Münster, Germany.
Archiv der Pharmazie
|June 18, 2024
概括
合成了新的环[g]类联体,以准GluN2B受体. 脂友性修饰显著增强了结合亲和力,显示出对其他受体位点的选择性.
科学领域:
- 药用化学 医学化学
- 神经科学是一个神经科学.
- 有机合成 有机合成
背景情况:
- NMDA受体的GluN2B亚单元是神经系统疾病的目标.
- 现有的配体如ifenprodil和Ro 25-6981具有部分和灵活的结构.
- 需要新的GluN2B配体,具有改进的特性和选择性.
研究的目的:
- 设计和合成新型环[g]类衍生物作为潜在的GluN2B配体.
- 为了在生物异构学上用类系统替换类组.
- 通过结合环丹环来减少形状的灵活性.
主要方法:
- 通过八步序列合成环[g]诺.
- 关键反应包括分子内弗里德尔 - 克拉夫茨化和曼尼赫反应.
- 亲和力和选择性使用结合性试验进行了评估.
主要成果:
- 最初的奇诺隆衍生物显示出中度的GluN2B亲和力.
- 引入脂性替代剂,特别是基和基基甲基组,使其亲和力增加了10倍以上.
- 化合物cis-13c和13e表现出高的GluN2B亲和力 (Ko=36 nM和27 nM,分别).
- 所有合成的化合物都显示出对NMDA受体的环丁 (PCP) 结合部位的选择性.
- 基衍生物13c对σ1和σ2受体表现出选择性.
结论:
- 环[g]基诺是开发GluN2B配体的有希望的支架.
- 脂友性N替代对于增强GluN2B亲和力至关重要.
- 开发的化合物表现出有利的选择性概况,需要进一步研究.
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