Synthesis and Biological Evaluation of a Selective N- and P/Q-Type Calcium Channel Agonist

被引:21
作者
Liang, Mary [1 ]
Tarr, Tyler B. [2 ,3 ]
Bravo-Altamirano, Karla [1 ]
Valdomir, Guillermo [1 ]
Rensch, Gabriel [1 ]
Swanson, Lauren [1 ]
DeStefino, Nicholas R. [2 ,3 ]
Mazzarisi, Cara M. [2 ,3 ]
Olszewski, Rachel A. [2 ,3 ]
Wilson, Gabriela Mustata [4 ]
Meriney, Stephen D. [2 ,3 ]
Wipf, Peter [1 ]
机构
[1] Univ Pittsburgh, Dept Chem, Pittsburgh, PA 15260 USA
[2] Univ Pittsburgh, Dept Neurosci, Pittsburgh, PA 15260 USA
[3] Univ Pittsburgh, Ctr Neurosci, Pittsburgh, PA 15260 USA
[4] Univ Pittsburgh, Dept Computat & Syst Biol, Pittsburgh, PA 15260 USA
来源
ACS MEDICINAL CHEMISTRY LETTERS | 2012年 / 3卷 / 12期
基金
美国国家卫生研究院; 美国国家科学基金会;
关键词
N/P/Q-type calcium channels; roscovitine; cdk2; selective agonist; Lambert-Eaton myasthenic syndrome; LEMS; neurological autoimmune disorder; EATON MYASTHENIC SYNDROME; CYCLIN-DEPENDENT KINASES; PRESYNAPTIC CALCIUM; TRANSMITTER RELEASE; ROSCOVITINE; INHIBITORS; PURINES; NEURONS; CR8;
D O I
10.1021/ml3002083
中图分类号
R914 [药物化学];
学科分类号
100701 ;
摘要
The acute effect of the potent cyclin-dependent kinase (cdk) inhibitor (R)-roscovitine on Ca2+ channels inspired the development of structural analogues as a potential treatment for motor nerve terminal dysfunction. On the basis of a versatile chlorinated purine scaffold, we have synthesized ca. 20 derivatives and characterized their N-type Ca2+ channel agonist action. Agents that showed strong agonist effects were also characterized in a kinase panel for their off-target effects. Among several novel compounds with diminished cdk activity, we identified a new lead structure with a 4-fold improved N-type Ca2+ channel agonist effect and a 22-fold decreased cdk2 activity as compared to (R)-roscovitine. This compound was selective for agonist activity on N- and P/Q-type over L-type calcium channels.
引用
收藏
页码:985 / 990
页数:6
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