ACS medicinal chemistry letters · 2012
Synthesis and biological evaluation of a selective N- and p/q-type calcium channel agonist.
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Liang Mary, Tarr Tyler B, Bravo-Altamirano Karla, Valdomir Guillermo, Rensch Gabriel, Swanson Lauren, DeStefino Nicholas R, Mazzarisi Cara M, Olszewski Rachel A, Wilson Gabriela Mustata, Meriney Stephen D, Wipf Peter
Аннотация
The acute effect of the potent cyclin-dependent kinase (cdk) inhibitor (R)-roscovitine on Ca(2+) 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 Ca(2+) 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 Ca(2+) 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.