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

The acute effect of the potent cyclin-dependent kinase (cdk) inhibitor (<i>R</i>)-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 (<i>R</i>)-roscovitine. This compound was selective for agonist activity on N- and P/Q-type over L-type calcium channels