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

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

1,†
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3
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4
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2
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5,*  and 1,*
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.
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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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