Synthesis and biological evaluation of a selective N- and p/q-type calcium channel agonist

ACS Med Chem Lett. 2012 Oct 1;3(12):985-90. doi: 10.1021/ml3002083. eCollection 2012 Dec 13.


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.

Keywords: LEMS; Lambert−Eaton myasthenic syndrome; N/P/Q-type calcium channels; cdk2; neurological autoimmune disorder; roscovitine; selective agonist.

Grant support

National Institutes of Health, United States