Action of clathrodin and analogues on voltage-gated sodium channels.
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.
Catholic University Leuven (KULeuven), Toxicology and Pharmacology, Herestraat 49-Box 922, 3000 Leuven, Belgium. steve.peigneur@pharm.kuleuven.be.
Steve
S
Peigneur
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. ales.zula@ffa.uni-lj.si.
Aleš
A
Zula
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. nace.zidar@ffa.uni-lj.si.
Nace
N
Zidar
Xention Ltd., Iconix Park, London Road, Pampisford, Cambridge CB22 3EG, UK. fionachan31@yahoo.co.uk.
Fiona
F
Chan-Porter
Xention Ltd., Iconix Park, London Road, Pampisford, Cambridge CB22 3EG, UK. robert.kirby@xention.com.
Robert
R
Kirby
Xention Ltd., Iconix Park, London Road, Pampisford, Cambridge CB22 3EG, UK. david.madge@xention.com.
David
D
Madge
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. janez.ilas@ffa.uni-lj.si.
Janez
J
Ilaš
University of Ljubljana, Faculty of Pharmacy, Aškerčeva 7, 1000 Ljubljana, Slovenia. danijel.kikelj@ffa.uni-lj.si.
Danijel
D
Kikelj
Catholic University Leuven (KULeuven), Toxicology and Pharmacology, Herestraat 49-Box 922, 3000 Leuven, Belgium. jan.tytgat@pharm.kuleuven.be.
Jan
J
Tytgat
D000818:Animals; D015195:Drug Design; D005260:Female; D018408:Patch-Clamp Techniques; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D061566:Voltage-Gated Sodium Channels / Q000187:drug effects* / Q000378:metabolism; D014982:Xenopus laevis
D011758:Pyrroles; D061566:Voltage-Gated Sodium Channels; C077211:clathrodin