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

• Main Authors: Peter J. Duggan, Aijun Yang, Irina Vetter, Jeffrey R. McArthur, Richard J. Lewis, Kellie L. Tuck, Jonathan B. Baell, Charlotte Elisabet Tranberg
• Format: Article
• Language: English
• Published: MDPI AG 2012-10-01
• Series: Marine Drugs
• Subjects: Cav2.2; conotoxin; peptidomimetics; radioligand binding; Ca2+ fluorescence assay; patch clamp electrophysiology
• Online Access: http://www.mdpi.com/1660-3397/10/10/2349
• ISSN: 1660-3397

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.