Medicinal Chemistry Research

, Volume 24, Issue 6, pp 2366–2380 | Cite as

Synthesis and biological evaluation of piperazine derivatives as novel isoform selective voltage-gated sodium (Nav) 1.3 channel modulators

  • Marko Jukič
  • Rok Frlan
  • Fiona Chan
  • Robert W. Kirby
  • David J. Madge
  • Jan Tytgat
  • Steve Peigneur
  • Marko AnderluhEmail author
  • Danijel Kikelj
Original Research


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 Nav 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 Nav 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 Nav 1.3, Nav 1.4, cardiac Nav 1.5, and Nav 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 Nav 1.3 channel isoform. The most potent compound showed selective activity against the Nav 1.3 channel isoform with an IC50 of 19 μM and is a suitable starting point for further development of selective Nav 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.


Voltage-gated Sodium channels Nav channels Nav channel modulators Isoform selective modulators Piperazine derivatives 



This work was supported by the European Union FP7 Integrated Project MAREX: Exploring Marine Resources for Bioactive Compounds: From Discovery to Sustainable Production and Industrial Applications (Project No. FP7-KBBE-2009-3-245137). We thank OpenEye Scientific Software, Inc. for free academic licenses of their software.


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Copyright information

© Springer Science+Business Media New York 2014

Authors and Affiliations

  • Marko Jukič
    • 1
  • Rok Frlan
    • 1
  • Fiona Chan
    • 2
  • Robert W. Kirby
    • 2
  • David J. Madge
    • 2
  • Jan Tytgat
    • 3
  • Steve Peigneur
    • 3
  • Marko Anderluh
    • 1
    Email author
  • Danijel Kikelj
    • 1
  1. 1.Faculty of PharmacyUniversity of LjubljanaLjubljanaSlovenia
  2. 2.Xention LimitedPampisfordUK
  3. 3.University of Leuven (KULeuven), Toxicology & Pharmacology O&N2LouvainBelgium

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