Structure-activity relationships of ?-conotoxins at N-type voltage-sensitive calcium channels

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Abstract
Due to their selectivity towards voltage‐sensitive calcium channels (VSCCs) ω‐conotoxins are being exploited as a new class of therapeutics in pain management and may also have potential application in ischaemic brain injury. Here, the structure–activity relationships (SARs) of several ω‐conotoxins including GVIA, MVIIA, CVID and MVIIC are explored. In addition, the three‐dimensional structures of these ω‐conotoxins and some structurally related peptides that form the cysteine knot are compared, and the effects of the solution environment on structure discussed. The diversity of binding and functional assays used to measure ω‐conotoxin potencies at the N‐type VSCC warranted a revaluation of the relationship between these assays. With one exception, [A22]‐GVIA, this analysis revealed a linear correlation between functional (peripheral N‐type VSCCs) and radioligand binding assays (central N‐type VSCCs) for the ω‐conotoxins and analogues that were tested over three studies. The binding and functional results of several studies are compared in an attempt to identify and distinguish those residues that are important in ω‐conotoxin function as opposed to those that form part of the structural scaffold. Further to determining what ω‐conotoxin residues are important for VSCC binding, the range of possible interactions between the ligand and channel are considered and the factors that influence the selectivity of MVIIA, GVIA and CVID towards N‐type VSCCs examined. Copyright © 2000 John Wiley & Sons, Ltd.