title: Evaluation of a novel calcium channel agonist for therapeutic potential in Lambert-Eaton myasthenic syndrome.
abstract: We developed a novel calcium (Ca(2+)) channel agonist that is selective for N- and P/Q-type Ca(2+) channels, which are the Ca(2+) channels that regulate transmitter release at most synapses. We have shown that this new molecule (GV-58) slows the deactivation of channels, resulting in a large increase in presynaptic Ca(2+) entry during activity. GV-58 was developed as a modification of (R)-roscovitine, which was previously shown to be a Ca(2+) channel agonist, in addition to its known cyclin-dependent kinase activity. In comparison with the parent molecule, (R)-roscovitine, GV-58 has a ∼20-fold less potent cyclin-dependent kinase antagonist effect, a ∼3- to 4-fold more potent Ca(2+) channel agonist effect, and ∼4-fold higher efficacy as a Ca(2+) channel agonist. We have further evaluated GV-58 in a passive transfer mouse model of Lambert-Eaton myasthenic syndrome and have shown that weakened Lambert-Eaton myasthenic syndrome-model neuromuscular synapses are significantly strengthened following exposure to GV-58. This new Ca(2+) channel agonist has potential as a lead compound in the development of new therapeutic approaches to a variety of disorders that result in neuromuscular weakness.
authors.affiliation: Department of Neuroscience, Center for Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.
authors.forename: Tyler B
authors.initials: TB
authors.lastname: Tarr
authors.forename: Waqas
authors.initials: W
authors.lastname: Malick
authors.forename: Mary
authors.initials: M
authors.lastname: Liang
authors.forename: Guillermo
authors.initials: G
authors.lastname: Valdomir
authors.forename: Michael
authors.initials: M
authors.lastname: Frasso
authors.forename: David
authors.initials: D
authors.lastname: Lacomis
authors.forename: Stephen W
authors.initials: SW
authors.lastname: Reddel
authors.forename: Adolfo
authors.initials: A
authors.lastname: Garcia-Ocano
authors.forename: Peter
authors.initials: P
authors.lastname: Wipf
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Meriney
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D000328:Adult; D000368:Aged; D000818:Animals; D002120:Calcium Channel Agonists / Q000627:therapeutic use*; D002460:Cell Line; D018844:Cyclin-Dependent Kinases / Q000037:antagonists & inhibitors; D003627:Data Interpretation, Statistical; D055724:Electrophysiological Phenomena / Q000187:drug effects; D006801:Humans; D015624:Lambert-Eaton Myasthenic Syndrome / Q000188:drug therapy*; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009469:Neuromuscular Junction / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism; D018408:Patch-Clamp Techniques; D010770:Phosphotransferases / Q000378:metabolism; D011687:Purines / Q000627:therapeutic use*; D000077546:Roscovitine; D013876:Thiophenes / Q000627:therapeutic use*
chemical_list: D002120:Calcium Channel Agonists; C583131:GV-58 compound; D018377:Neurotransmitter Agents; D011687:Purines; D013876:Thiophenes; D000077546:Roscovitine; D010770:Phosphotransferases; D018844:Cyclin-Dependent Kinases