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Design and Biological Evaluation of a New Calcium Channel Agonist

详细技术说明

None

*Abstract

BackgroundLambert Eaton Myasthenic Syndrome, LEMS, is a neurological autoimmune disorder of the neuromuscular junction (NMJ). The disease is characterized by a reduction of presynaptic calcium channels and results in progressive muscle weakness that affects everyday activities and quality of life. While LEMS is a relatively rare disease, its true incidence rate remains unknown as it is often undiagnosed inpatients. Furthermore, current treatment options are symptomatic, only modestly effective, and with significant side effects.Technology DescriptionThe innovators developed GV-58, as a first-in-class, use-dependent, Ca2 channel agonist selective for the types of Ca2 channels that control neurotransmitter release. GV-58 has great potential to treat neuromuscular weakness such as LEMS. GV-58 does not directly open Ca2 channels in the absence of depolarization; it increases mean open time only after they open. This voltage-dependent (or use-dependent) action is critical to the use of GV-58 as a therapeutic, especially when used synergistically with the potassium channel blocker 3,4-diaminopyridine (DAP).Advantages1. Potential to treat the muscle weakness associated with LEMS2. In comparison with the parent molecule, R-roscovitine, GV-58 has a 20-fold less potent cyclin-dependent kinase antagonist effect, and 4-fold higher efficacy as a CA2 channel agonistApplication1. Therapeutic option for Lambert-Eaton Myasthenic Syndrome2. Potential to treat a variety of disorders that result in neuromuscular weaknessStage of DevelopmentIn-Vivo Studies in Murine ModelsPublications1. Tarr TB, Lacomis D, Reddel SW, Liang M, Valdomir G, Frasso M, Wipf P, Meriney SD. Complete reversal of Lambert-Eaton myasthenic syndrome synaptic impairment by the combined use of a K channel blocker and a Ca2 channel agonist. J Physiol. 2014 Aug 15;592(Pt 16):3687-96. doi: 10.1113/jphysiol.2014.276493. Epub 2014 Jul 11. PubMed PMID: 25015919; PubMed Central PMCID: PMC4229355.2. Tarr TB, Malick W, Liang M, Valdomir G, Frasso M, Lacomis D, Reddel SW, Garcia-Ocano A, Wipf P, Meriney SD. Evaluation of a novel calcium channel agonist for therapeutic potential in Lambert-Eaton myasthenic syndrome. J Neurosci. 2013 Jun 19;33(25):10559-67. doi: 10.1523/JNEUROSCI.4629-12.2013. PubMed PMID: 23785168; PubMed Central PMCID: PMC3685843.PCT Application Filed

*Principal Investigation

Name: Mary Liang

Department: Pharm-Pharmaceutical Science

Name: Stephen Meriney

Department: Neuroscience

Name: Peter Wipf, Professor

Department: Chemistry

国家/地区

美国