title: Synthesis and biological evaluation of a selective N- and p/q-type calcium channel agonist.
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.
authors.affiliation: 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.
authors.forename: Mary
authors.initials: M
authors.lastname: Liang
authors.affiliation: 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.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Tarr
authors.affiliation: 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.
authors.forename: Karla
authors.initials: K
authors.lastname: Bravo-Altamirano
authors.affiliation: 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.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Valdomir
authors.affiliation: 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.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Rensch
authors.affiliation: 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.
authors.forename: Lauren
authors.initials: L
authors.lastname: Swanson
authors.affiliation: 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.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: DeStefino
authors.affiliation: 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.
authors.forename: Cara M
authors.initials: CM
authors.lastname: Mazzarisi
authors.affiliation: 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.
authors.forename: Rachel A
authors.initials: RA
authors.lastname: Olszewski
authors.affiliation: 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.
authors.forename: Gabriela Mustata
authors.initials: GM
authors.lastname: Wilson
authors.affiliation: 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.
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Meriney
authors.affiliation: 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.
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
keywords: LEMS; Lambert−Eaton myasthenic syndrome; N/P/Q-type calcium channels; cdk2; neurological autoimmune disorder; roscovitine; selective agonist