Synthesis and Cav2.2 Binding Data for Non-Peptide Mimetics of ω-Conotoxin GVIA based on a 5-Amino-Anthranilamide Core

Abstract

A simple and efficient method has been developed for the synthesis of two anthranilamide-based non-peptide mimetics of ω-conotoxin GVIA. These anthranilamide derivatives aim to mimic the K2, R17, and Y13 residues of the peptide. The synthetic route described enables the rapid synthesis of anthranilamide analogues with identical alkyl chain lengths. The target compounds show affinity to rat N-type voltage gated calcium channels (Cav2.2) with EC50 values of 42 and 75 μM.

ω-Conotoxin GVIA mimetics based on an anthranilamide core: Effect of variation in ammonium side chain lengths and incorporation of fluorine

“…17,19,21,28 The results are summarised in Table 1 In the original investigation of the use of the anthranilamide scaffold in x-conotoxin GVIA mimicry, the design strategy was tested with two compounds (1a and 1b). 17 The observation now of several analogues of 1a with Ca v 2.2 affinities of <20 lM supports the a,b-bond vector approach to N-type channel blockers and confirms the suitability of the anthranilamide core as a scaffold with which to develop lead structures.…”

“…Along these lines, we have recently shown that activity is retained if one of the ether links in 1b is changed to an amide. 19 Encouraged by the calcium channel affinity shown by long-chain aliphatic amines like dodecylamine, 20 here we describe the preparation and Ca v 2.2 affinity of a series of analogues of 1a and 1b where variation occurs in the length of ammonium side chains. This has been extended to the preparation and testing of an analogue that bears a fluorine substituent on the peripheral aromatic moiety.…”

Strategies for the Development of Conotoxins as New Therapeutic Leads

“…The functionalized molecule bearing the Try13, Arg17 and Lys2 side chain mimics blocked Ca V 2.2 with micromolar affinity in a functional assay (68 μM) [41]. Further structure-activity relationship (SAR) studies surrounding the mimetic focused on the nature of the alkyl side chains and the use of both amino and guanidine groups [42,43]. Variation of the side chain lengths of both the Lys and Arg mimics did not generate any convincing SAR, although varying the terminal functionality on the Lys and Arg side chains did significantly affect activity.…”

Targeting voltage‐gated calcium channels: developments in peptide and small‐molecule inhibitors for the treatment of neuropathic pain

“…Several approaches have been undertaken, including the positioning of mimetics of Tyr13, Leu11 and Arg10 of MVIIA around a dendritic backbone (Menzler et al ., 1998; 2000; Guo et al ., 2000), the rational design of type‐III mimetics of GVIA based on Lys2, Tyr13 and Arg17 side chains (Baell et al ., 2001; 2004; 2006; Duggan et al ., 2008; 2009; Andersson et al ., 2009), and the grafting of important GVIA residues onto the backbone structure of contryphan‐R (Figure 4) (Pallaghy and Norton, 2000). Although the functional groups of the important loop 2 residues were retained, the resulting molecules failed to possess the potency of the native ω‐conotoxins.…”