Sesterterpene glycinyl-lactams: A new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia

Md Islam, Walter Balansa, Frank Fontaine, Andrew M Piggott, Hua Zhang, Xue Xiao, Timothy I. Webb, Daniel F Gilbert, Joseph W Lynch, Robert J Capon

Research output: Contribution to journalArticle

Abstract

Bioassay guided fractionation of three southern Australian marine sponges of the genus Psammocinia, selected for their ability to modulate glycine-gated chloride channel receptors (GlyRs), yielded the rare marine sesterterpenes (−)-ircinianin (1) and (−)-ircinianin sulfate (2), along with the new biosynthetically
related metabolites (−)-ircinianin lactam A (3), (−)-ircinianin lactam A sulfate (4), (−)-oxoircinianin (5), (−)-oxoircinianin lactam A (6) and (−)-ircinianin lactone A (7). Acetylation of 1 returned (−)-ircinianin acetate (8). Whole cell patch-clamp electrophysiology on 1–8 established 3 as an exceptionally potent and selective α3 GlyR potentiator, and 6 as a selective α1 GlyR potentiator. The discovery and characterization of sesterterpenes 1–8, and in particular the glycinyl-lactams 3 and 6, provide valuable new insights into GlyR pharmacology. These insights have the potential to inform and inspire the development of new molecular tools to probe GlyR distribution and function, and therapeutics to treat a wide array of GlyR mediated diseases and disorders.
Original languageEnglish
Pages (from-to)4695-4701
Number of pages7
JournalOrganic & Biomolecular Chemistry
Volume11
Issue number28
DOIs
Publication statusPublished - 2013
Externally publishedYes

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    Islam, M., Balansa, W., Fontaine, F., Piggott, A. M., Zhang, H., Xiao, X., Webb, T. I., Gilbert, D. F., Lynch, J. W., & Capon, R. J. (2013). Sesterterpene glycinyl-lactams: A new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia. Organic & Biomolecular Chemistry, 11(28), 4695-4701. https://doi.org/10.1039/C3OB40861B