Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Mar Drugs
2014 Mar 28;124:2132-43. doi: 10.3390/md12042132.
Show Gene links
Show Anatomy links
Action of clathrodin and analogues on voltage-gated sodium channels.
Peigneur S
,
Zula A
,
Zidar N
,
Chan-Porter F
,
Kirby R
,
Madge D
,
Ilaš J
,
Kikelj D
,
Tytgat J
.
???displayArticle.abstract???
Clathrodin is a marine alkaloid and believed to be a modulator of voltage-gated sodium (Na(V)) channels. Since there is an urgent need for small molecule Na(V) channel ligands as novel therapeutics, clathrodin could represent an interesting lead compound. Therefore, clathrodin was reinvestigated for its potency and Na(V) channel subtype selectivity. Clathrodin and its synthetic analogues were subjected to screening on a broad range of Na(V) 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 Na(V) channels, hereby validating the pyrrole-2-aminoimidazole alkaloid structure as a core structure for future small molecule-based Na(V) channel modulators.
Figure 1. Structures of clathrodin (1), oroidin (2), hymenidin (3), dihydroclathrodin (4) and synthetic Analogues 5, 6, 7, 8 and 9 are shown.
Figure 2. Activity profile of clathrodin on several NaV channel isoforms. Representative whole-cell current traces in control and compound conditions are shown. The dotted line indicates the zero-current level. The arrow marks steady-state current traces after the application of 10 μM of clathrodin. The traces shown are representative traces of at least three independent experiments (n ≥ 3).
Figure 3. Activity profile of Compound 8 on several NaV channel isoforms. Representative whole-cell current traces in control and compound conditions are shown. The dotted line indicates the zero-current level. The arrow marks steady-state current traces after the application of 10 μM of Compound 8. The traces shown are representative traces of at least three independent experiments (n ≥ 3).
Figure 4. Electrophysiological characterization of Compound 8 on NaV1.4 (A,C) and NaV1.6 (B) channels under voltage clamp (A,B) and patch clamp (C) conditions. (A, left panel) Representative whole-cell current traces of NaV1.4 in control and 10 μM of Compound 8 conditions are shown; (right panel) steady-state activation and inactivation curves in control (closed symbols) and compound conditions (open symbols). (B, left panel) Representative whole-cell current traces of NaV1.6 in control and 250 μM of Compound 8 conditions are shown; (right panel) steady-state activation and inactivation curves in control (closed symbols) and compound conditions (open symbols). (C) Representative current traces of NaV1.4 in the control and 10 μM of compound conditions are shown in the resting state (left panel) and the inactivated state (right panel). The asterisk (*) marks the steady-state current traces after the application of 10 μM of Compound 8.
Figure 5. Electrophysiological characterization of Compound 9 under voltage clamp (A) and patch clamp (C) conditions. (A) Representative whole-cell current traces of NaV1.4 and NaV1.5 in the control and 1 μM of Compound 9 conditions are shown. The asterisk (*) marks the steady-state current traces after the application of 1 μM of Compound 9. (B, left panel) At a 1-μM concentration of Compound 9, no significant alteration in the characteristics of activation or inactivation was observed; (B, right panel) The concentration-response curve of Compound 9 for NaV1.4 channels. The IC50 value yielded 3.5 ± 0.9 μM. (C) The representative current traces of NaV1.4 in the control and 10 μM of Compound 9 conditions are shown in the resting state (left panel) and the inactivated state (right panel). The asterisk (*) marks the steady-state current traces after the application of 10 μM of Compound 9.
Andavan,
Voltage-gated sodium channels: mutations, channelopathies and targets.
2011, Pubmed
Andavan,
Voltage-gated sodium channels: mutations, channelopathies and targets.
2011,
Pubmed
Catterall,
Voltage-gated sodium channels at 60: structure, function and pathophysiology.
2012,
Pubmed
Chi,
Development of a sea anemone toxin as an immunomodulator for therapy of autoimmune diseases.
2012,
Pubmed
Du,
Identification of new batrachotoxin-sensing residues in segment IIIS6 of the sodium channel.
2011,
Pubmed
,
Xenbase
Kobayashi,
A novel antagonist of serotonergic receptors, hymenidin, isolated from the Okinawan marine sponge Hymeniacidon sp.
1986,
Pubmed
Liman,
Subunit stoichiometry of a mammalian K+ channel determined by construction of multimeric cDNAs.
1992,
Pubmed
,
Xenbase
McCormack,
Voltage sensor interaction site for selective small molecule inhibitors of voltage-gated sodium channels.
2013,
Pubmed
Moczydlowski,
The molecular mystique of tetrodotoxin.
2013,
Pubmed
Nardi,
Advances in targeting voltage-gated sodium channels with small molecules.
2012,
Pubmed
Olofson,
Synthesis of Mauritiamine.
1997,
Pubmed
Pope,
Ziconotide: a clinical update and pharmacologic review.
2013,
Pubmed
Rentas,
Effect of alkaloid toxins from tropical marine sponges on membrane sodium currents.
1995,
Pubmed
Rodríguez de la Vega,
Overview of scorpion toxins specific for Na+ channels and related peptides: biodiversity, structure-function relationships and evolution.
2005,
Pubmed
Schroif-Gregoire,
Direct access to marine pyrrole-2-aminoimidazoles, oroidin, and derivatives, via new acyl-1,2-dihydropyridin intermediates.
2006,
Pubmed
Stevens,
Neurotoxins and their binding areas on voltage-gated sodium channels.
2011,
Pubmed
Tikhonov,
Sodium channel activators: model of binding inside the pore and a possible mechanism of action.
2005,
Pubmed
Tomašić,
Ligand- and structure-based virtual screening for clathrodin-derived human voltage-gated sodium channel modulators.
2013,
Pubmed
Žula,
2-Aminoimidazoles in medicinal chemistry.
2013,
Pubmed
