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Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Nav) 1.3 channel modulators
Jukic, M.; Frlan, R.; Chan, F.; Kirby, R.; Madge, D.; Tytgat, J.; Peigneur, S.; Anderluh, M.; Kikelj, D. (2015). Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Nav) 1.3 channel modulators. Med. Chem. Res. 24(6): 2366-2380.
In: Medicinal Chemistry Research. Springer/Birkhaeuser Boston: Cambridge. ISSN 1054-2523, more
Peer reviewed article  

Available in  Authors 
    VLIZ: Open Repository 292280 [ OMA ]

Author keywords
    Voltage-gated; Sodium channels; Na-v channels; Na-v channel modulators;Isoform selective modulators; Piperazine derivatives

Authors  Top 
  • Jukic, M.
  • Frlan, R.
  • Chan, F.
  • Kirby, R.
  • Madge, D.
  • Tytgat, J., more
  • Peigneur, S., more
  • Anderluh, M.
  • Kikelj, D.

    Sponges of the genus Agelas produce compounds that modulate the activity of voltage-gated sodium ion channels and contribute novel scaffolds for the development of compounds with activity against a plethora of biological targets. In particular, clathrodin and dibromosceptrin were reported to decrease the average maximum amplitude of inward sodium currents in isolated chick embryo sympathetic ganglia cells; we envisaged these compounds as a starting point to design novel Na-v channel modulators. This endeavor was part of our long-term goal of designing a comprehensive library of Agelas alkaloid analogs that would cover a broader chemical space and allow us to examine the activity of such compounds on Na-v channels. Our series of compounds was designed by maintaining the terminal structural features found in clathrodin while rigidizing the central part of the molecule and replacing the 3-aminopropene linker with a 4-methylenepiperazine moiety. Synthesised compounds were screened for inhibitory action against the human voltage-gated sodium channel isoforms Na-v 1.3, Na-v 1.4, cardiac Na-v 1.5, and Na-v 1.7 using an automated patch clamp electrophysiology technique. The results demonstrate that we have obtained a series of compounds with a modest but selective inhibitory activity against the Na-v 1.3 channel isoform. The most potent compound showed selective activity against the Na-v 1.3 channel isoform with an IC50 of 19 mu M and is a suitable starting point for further development of selective Na-v 1.3 channel modulators. Such compounds could prove to be beneficial as a pharmacological tool towards the development of novel therapeutically useful compounds in the treatment of pain.

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