共 28 条
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.
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页码:985 / 990
页数:6
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