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7189824 
Journal Article 
Evaluation of a Novel Calcium Channel Agonist for Therapeutic Potential in Lambert-Eaton Myasthenic Syndrome 
Tarr, TB; Meriney, SD; Malick, W; Liang, M; Valdomir, G; Frasso, M; Lacomis, D; Reddel, SW; Garcia-Ocano, A; Wipf, P; , 
2013 
Yes 
Journal of Neuroscience
ISSN: 0270-6474
EISSN: 1529-2401 
SOC NEUROSCIENCE 
WASHINGTON 
33 
25 
10559-10567 
English 
23785168 
WOS:000320596400035 
We developed a novel calcium (Ca2+) channel agonist that is selective for N- and P/Q-type Ca2+ channels, which are the Ca2+ 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 Ca2+ entry during activity. GV-58 was developed as a modification of (R)-roscovitine, which was previously shown to be a Ca2+ channel agonist, in addition to its known cyclin-dependent kinase activity. In comparison with the parent molecule, (R)-roscovitine, GV-58 has a similar to 20-fold less potent cyclin-dependent kinase antagonist effect, a similar to 3- to 4-fold more potent Ca2+ channel agonist effect, and similar to 4-fold higher efficacy as a Ca2+ 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 Ca2+ 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.