Action of Clathrodin and Analogues on Voltage-Gated Sodium Channels

Steve Peigneur,Janez Ilaš,Danijel Kikelj,David Madge,Jan Tytgat,Fiona Chan-Porter,Aleš Žula,Robert Kirby,Nace Zidar

doi:10.3390/md12042132

Steve Peigneur, Janez Ilaš + Show 7 more

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https://doi.org/10.3390/md12042132

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Abstract

Clathrodin is a marine alkaloid and believed to be a modulator of voltage-gated sodium (NaV ) channels. Since there is an urgent need for small molecule NaV channel ligands as novel therapeutics, clathrodin could represent an interesting lead compound. Therefore, clathrodin was reinvestigated for its potency and NaV channel subtype selectivity. Clathrodin and its synthetic analogues were subjected to screening on a broad range of NaV channel isoforms, both in voltage clamp and patch clamp conditions. Even though clathrodin was not found to exert any activity, some analogues were capable of modulating the NaV channels, hereby validating the pyrrole-2-aminoimidazole alkaloid structure as a core structure for future small molecule-based NaV channel modulators.

Highlights

Marine organisms, such as sea anemones, cone snails, fish, algae and sponges, among others, are known to produce peptide and non-peptide toxins targeting ion channels
No activity was observed for clathrodin, oroidin, hymenidin or the analogues, 4, 5, 6 and 7, even at concentrations up to 10 μM (Figure 2)
There is increasing evidence regarding the important role of NaV channels in channelopathies, and their crucial contribution in chronic pain

Summary

Introduction

Marine organisms, such as sea anemones, cone snails, fish, algae and sponges, among others, are known to produce peptide and non-peptide toxins targeting ion channels. The majority of marine toxins have been characterized to act upon voltage-gated sodium (NaV) channels. These molecules exhibit their toxicity by either physically inhibiting the sodium ion flow through the channel or by modifying the kinetics of channel gating [1]. Clathrodin was shown, in experiments performed in cells isolated from chick embryo sympathetic ganglia using the whole cell configuration of the patch clamp technique, to possess neurotoxic activity. It decreased the average maximum amplitudes of isolated inward sodium currents by 30% Clathrodin (1) is a 2-aminoimidazole alkaloid containing an unsubstituted pyrrole 2-carboxamide moiety, isolated from the Caribbean sea sponge, Agelas clathrodes, which is structurally related to its 2,3-dibromopyrrole analogue, oroidin, from the sponge, Agelas oroides, and 2-bromopyrrole analogue hymenidin from the sponge, Hymeniacidon sp. [2,3,4].

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