Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator

Walter Balansa, Robiul Islam, Daniel F. Gilbert, Frank Fontaine, Xue Xiao, Hua Zhang, Andrew M. Piggott, Joseph W. Lynch, Robert J. Capon*

*Corresponding author for this work

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Chemical analysis of a specimen of the sponge Ianthella cf. flabelliformis returned two new sesquiterpene glycinyl lactams, ianthellalactams A (1) and B (2), the known sponge sesquiterpene dictyodendrillin (3) and its ethanolysis artifact ethyl dictyodendrillin (4), and five known sponge indole alkaloids, aplysinopsin (5), 8E-3′-deimino-3′-oxoaplysinopsin (6), 8Z-3′-deimino-3′-oxoaplysinopsin (7), dihydroaplysinopsin (8) and tubastrindole B (9). The equilibrated mixture 6/7 exhibited glycine-gated chloride channel receptor (GlyR) antagonist activity with a bias towards α3 over α1 GlyR, while tubastrindole B (9) exhibited a bias towards α1 over α3 GlyR. At low- to sub-micromolar concentrations, 9 was also a selective potentiator of α1 GlyR, with no effect on α3 GlyR - a pharmacology that could prove useful in the treatment of movement disorders such as spasticity and hyperekplexia. Our investigations into the GlyR modulatory properties of 1-9 were further supported by the synthesis of a number of structurally related indole alkaloids.

Original languageEnglish
Pages (from-to)4420-4425
Number of pages6
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number14
DOIs
Publication statusPublished - 15 Jul 2013
Externally publishedYes

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Keywords

  • Glycine-gated chloride channel receptor modulators
  • Ianthella cf. flabelliformis
  • Marine natural products chemistry
  • Sesterterpene tetronic acid glycinyl lactams

Cite this

Balansa, W., Islam, R., Gilbert, D. F., Fontaine, F., Xiao, X., Zhang, H., ... Capon, R. J. (2013). Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator. Bioorganic and Medicinal Chemistry, 21(14), 4420-4425. https://doi.org/10.1016/j.bmc.2013.04.061