Evaluation of a Novel Calcium Channel Agonist for Therapeutic Potential in Lambert-Eaton Myasthenic Syndrome

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 ∼20-fold less potent cyclin-dependent kinase antagonist effect, a ∼3- to 4-fold more potent Ca²⁺ channel agonist effect, and ∼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.