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

• Published in: Medicinal chemistry research 2015-06, Vol.24 (6), p.2366-2380
• Main Authors: Jukič, Marko, Frlan, Rok, Chan, Fiona, Kirby, Robert W., Madge, David J., Tytgat, Jan, Peigneur, Steve, Anderluh, Marko, Kikelj, Danijel
• Format: Article
• Language: English
• Subjects: Biochemistry; Biomedical and Life Sciences; Biomedicine; Cell Biology; Original Research; Pharmacology/Toxicology
• ISSN: 1054-2523; 1554-8120
• DOI: 10.1007/s00044-014-1300-x

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 IC 50 of 19 μM 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.