title: ω-Conotoxin GVIA mimetics that bind and inhibit neuronal Ca(v)2.2 ion channels.
abstract: The neuronal voltage-gated N-type calcium channel (Ca(v)2.2) 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 Ca(v)2.2 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.
authors.affiliation: CSIRO Materials Science and Engineering, Bag 10, Clayton South, Victoria 3169, Australia.
authors.forename: Charlotte Elisabet
authors.initials: CE
authors.lastname: Tranberg
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Aijun
authors.initials: A
authors.lastname: Yang
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Irina
authors.initials: I
authors.lastname: Vetter
authors.affiliation: Health Innovations Research Institute, RMIT University, Melbourne, Victoria 3083, Australia.
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: McArthur
authors.affiliation: Medicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia.
authors.forename: Jonathan B
authors.initials: JB
authors.lastname: Baell
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia.
authors.forename: Richard J
authors.identifier: 0000-0003-3470-923X
authors.initials: RJ
authors.lastname: Lewis
authors.affiliation: School of Chemistry, Monash University, Clayton, Victoria 3800, Australia.
authors.forename: Kellie L
authors.initials: KL
authors.lastname: Tuck
authors.affiliation: CSIRO Materials Science and Engineering, Bag 10, Clayton South, Victoria 3169, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Duggan
mesh_terms: D020864:Calcium Channels, N-Type / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D055724:Electrophysiological Phenomena; D006801:Humans; D015394:Molecular Structure; D018408:Patch-Clamp Techniques; D013329:Structure-Activity Relationship; D020866:omega-Conotoxin GVIA / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: C500545:CACNA1B protein, human; D020864:Calcium Channels, N-Type; D020866:omega-Conotoxin GVIA