替代的2-氨基胺 选择性对α7-尼古丁性乙胆受体激活和与乙胆结合蛋白的关联
Katarzyna Kaczanowska1, Gisela Andrea Camacho Hernandez1,2, Larissa Bendiks1
1Department of Pharmacology, Skaggs School of Pharmacy & Pharmaceutical Sciences, University of California, San Diego , La Jolla, California 92093-0650, United States.
Journal of the American Chemical Society
|February 22, 2017
概括
研究人员开发了激活α7尼古丁乙胆受体 (α7-nAChR) 的新型2-氨基胺. 这些化合物具有特定的结合性,为针对尼古丁乙胆受体的新疗法提供了潜力.
科学领域:
- 神经科学
- 药理学
- 生物化学
背景情况:
- 尼古丁乙胆受体 (nAChR) 是各种生理过程中关联的关键离子通道.
- 之前的研究发现2-氨基胺基与乙胆结合蛋白 (AChBP) 合作结合,这是nAChRs的替代物.
研究的目的:
- 研究新型2-氨基胺衍生物对特定的nAChR亚型的受体相互作用.
- 识别具有α7-nAChR亚型选择性激素活性的化合物.
主要方法:
- 表达α7-nAChR,α4β2-nAChR和5-HT3AR的HEK细胞转染.
- 使用光传递器选50多种2-氨基胺基的受体激活.
- 联结体-AChBP复合物的联合结晶以分析结合模式.
主要成果:
- 两种2 - 氨基胺酸在10μM以下表现出α7- nAChR激应.
- 优化的衍生物实现了α7-nAChR激活的70 nM EC50和类似的ACBP K_d.
- 几种化合物表现出α7-nAChR特异性,在10μM时对α4β2-nAChR或5-HT3AR没有活性.
- 同结晶显示了在子单元界面上的明显的结合方向,与经典的配体不同.
结论:
- 新型2-氨基胺可以选择性地激活α7-nAChR.
- 鉴定到的结合姿势表明了在nAChR激动剂-对抗剂部位的新作用机制.
- 这些发现可能会导致对异构性nAChRs的异构调节剂的开发.
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