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

Marine Drugs

Charlotte Elisabet Tranberg⁵  Aijun Yang¹  Irina Vette¹  Jeffrey R. McArthur²  Jonathan B. Baell⁴  Richard J. Lewis¹  Kellie L. Tuck³ 

[1] Institute for Molecular Bioscience, The University of Queensland, St Lucia, QLD 4072, Australia;Health Innovations Research Institute, RMIT University, Melbourne, Victoria 3083, Australia;;School of Chemistry, Monash University, Clayton, Victoria 3800, AustraliaMedicinal Chemistry and Drug Action, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052, Australia;CSIRO Materials Science and Engineering, Bag 10, Clayton South, Victoria 3169, Australia;

关键词: Ca_v2.2;    conotoxin;    peptidomimetics;    radioligand binding;    Ca²⁺ fluorescence assay;    patch clamp electrophysiology;   

DOI  :  10.3390/md10102349

来源: mdpi

【 摘 要 】

The neuronal voltage-gated N-type calcium channel (Ca_v2.2) 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_v2.2 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.

【 授权许可】

CC BY   
© 2012 by the authors; licensee MDPI, Basel, Switzerland.