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New Cav2 Calcium Channel Gating Modifiers With Agonist Activity and Therapeutic Potential to Treat Neuromuscular Disease

New Cav2 Calcium Channel Gating Modifiers With Agonist Activity and Therapeutic Potential to Treat Neuromuscular Disease

Man Wu, Hayley V White, Blake A Boehm, Christopher J Meriney, Kaylan Kerrigan, Michael Frasso, Mary Liang, Erika M Gotway, Madeleine R Wilcox, Jon W Johnson, Peter Wipf, Stephen D Meriney

Neuropharmacology. 2018 Mar 15;131:176-189.

PMID: 29246857

Abstract:

Voltage-gated calcium channels (VGCCs) are critical regulators of many cellular functions, including the activity-dependent release of chemical neurotransmitter from nerve terminals. At nerve terminals, the Cav2 family of VGCCs are closely positioned with neurotransmitter-containing synaptic vesicles. The relationship between calcium ions and transmitter release is such that even subtle changes in calcium flux through VGCCs have a strong influence on the magnitude of transmitter released. Therefore, modulators of the calcium influx at nerve terminals have the potential to strongly affect transmitter release at synapses. We have previously developed novel Cav2-selective VGCC gating modifiers (notably GV-58) that slow the deactivation of VGCC current, increasing total calcium ion flux. Here, we describe ten new gating modifiers based on the GV-58 structure that extend our understanding of the structure-activity relationship for this class of molecules and extend the range of modulation of channel activities. In particular, we show that one of these new compounds (MF-06) was more efficacious than GV-58, another (KK-75) acts more quickly on VGCCs than GV-58, and a third (KK-20) has a mix of increased speed and efficacy. A subset of these new VGCC agonist gating modifiers can increase transmitter release during action potentials at neuromuscular synapses, and as such, show potential as therapeutics for diseases with a presynaptic deficit that results in neuromuscular weakness. Further, several of these new compounds can be useful tool compounds for the study of VGCC gating and function.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP1402821413	GV-58		1402821-41-3	Price

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