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Mar. Drugs 2012, 10(10), 2349-2368; https://doi.org/10.3390/md10102349

ω-Conotoxin GVIA Mimetics that Bind and Inhibit Neuronal Cav2.2 Ion Channels

1
CSIRO Materials Science and Engineering, Bag 10, Clayton South, Victoria 3169, Australia
2
Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia
3
Health Innovations Research Institute, RMIT University, Melbourne, Victoria 3083, Australia
4
Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia
5
School of Chemistry, Monash University, Clayton, Victoria 3800, Australia
Current address: Faculty of Science and Technology, Deakin University, Locked Bag 20000, Geelong, Victoria 3220, Australia.
*
Authors to whom correspondence should be addressed.
Received: 12 September 2012 / Revised: 10 October 2012 / Accepted: 12 October 2012 / Published: 22 October 2012
(This article belongs to the Special Issue Marine Peptides and Their Mimetics)
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Abstract

The neuronal voltage-gated N-type calcium channel (Cav2.2) is a validated target for the treatment of neuropathic pain. A small library of anthranilamide-derived ω-Conotoxin GVIA mimetics bearing the diphenylmethylpiperazine moiety were prepared and tested using three experimental measures of calcium channel blockade. These consisted of a 125I-ω-conotoxin GVIA displacement assay, a fluorescence-based calcium response assay with SH-SY5Y neuroblastoma cells, and a whole-cell patch clamp electrophysiology assay with HEK293 cells stably expressing human Cav2.2 channels. A subset of compounds were active in all three assays. This is the first time that compounds designed to be mimics of ω-conotoxin GVIA and found to be active in the 125I-ω-conotoxin GVIA displacement assay have also been shown to block functional ion channels in a dose-dependent manner. View Full-Text
Keywords: Cav2.2; conotoxin; peptidomimetics; radioligand binding; Ca2+ fluorescence assay; patch clamp electrophysiology Cav2.2; conotoxin; peptidomimetics; radioligand binding; Ca2+ fluorescence assay; patch clamp electrophysiology
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Tranberg, C.E.; Yang, A.; Vetter, I.; McArthur, J.R.; Baell, J.B.; Lewis, R.J.; Tuck, K.L.; Duggan, P.J. ω-Conotoxin GVIA Mimetics that Bind and Inhibit Neuronal Cav2.2 Ion Channels. Mar. Drugs 2012, 10, 2349-2368.

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