2. Academic Validation
  3. Synthesis and biological evaluation of a selective N- and p/q-type calcium channel agonist

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.
Mary Liang 1,  Tyler B Tarr 1,  Karla Bravo-Altamirano 1,  Guillermo Valdomir 1,  Gabriel Rensch 1,  Lauren Swanson 1,  Nicholas R DeStefino 1,  Cara M Mazzarisi 1,  Rachel A Olszewski 1,  Gabriela Mustata Wilson 1,  Stephen D Meriney 1,  Peter Wipf 1
Affiliations

Affiliation

  • 1 Department of Chemistry, Department of Neuroscience and Center for Neuroscience, and Department of Computational and Systems Biology, University of Pittsburgh , Pittsburgh, Pennsylvania 15260, United States.
PMID: 24936234 DOI: 10.1021/ml3002083
Abstract

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.

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