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

被引：23

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

页码：985 / 990

页数：6

共 28 条

[1] CR8, a potent and selective, roscovitine-derived inhibitor of cyclin-dependent kinases [J].