Evaluation of a novel calcium channel agonist for therapeutic potential in Lambert-Eaton myasthenic syndrome

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.