Inhibition of N-type calcium channels by phenoxyaniline and sulfonamide analogues

Figures

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  Fig. 1. Structures of gabapentin 1, pregabalin 2, ω-conotoxin MVIIA 3,7 marketed as ziconotide (Prialt®), Z160 4 and ABT-639 5.

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  Fig. 2. Chemical structures and their activity, determined by calcium influx fluorescence-imaging assays, of MONIRO-1 6a, and related analogues 6b, 7a and 7b, and the constrained analogues 8–10.

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  Fig. 3. Schematic depiction of the library of compounds synthesised and tested; replacement of the labile amide bond of MONIRO-1 6a with either a secondary aniline or an isosteric sulfonamide functional group, and replacement of the guanidinium group with less hydrophilic amines.

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  Scheme 1. Synthesis of the phenoxyaniline analogues 32–41.

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  Scheme 2. Synthesis of the sulfonamide analogues 42–51.

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  Fig. 4. Dose response curves, determined by calcium influx fluorescence-imaging assays of the sulfonamide compounds 42–51 in a) hCaV2.2 and b) hCaV3.2 channels. Data are presented as mean ± SEM from n = 3–5 independent experiments. The calculated IC50 values are shown in the relevant tables.