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

Balansa, Walter, Islam, Robiul, Gilbert, Daniel F., Fontaine, Frank, Xiao, Xue, Zhang, Hua, Piggott, Andrew M., Lynch, Joseph W. and Capon, Robert 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. doi:10.1016/j.bmc.2013.04.061

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Author Balansa, Walter
Islam, Robiul
Gilbert, Daniel F.
Fontaine, Frank
Xiao, Xue
Zhang, Hua
Piggott, Andrew M.
Lynch, Joseph W.
Capon, Robert J.
Title Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator
Journal name Bioorganic and Medicinal Chemistry   Check publisher's open access policy
ISSN 0968-0896
Publication date 2013-05-01
Year available 2013
Sub-type Article (original research)
DOI 10.1016/j.bmc.2013.04.061
Open Access Status
Volume 21
Issue 14
Start page 4420
End page 4425
Total pages 6
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon
Collection year 2014
Language eng
Formatted 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.
Keyword Glycine gated chloride channel receptor modulators
Lanthella cf. flabelliformis
Marine natural products chemistry
Sesterterpene tetronic acid glycinyl lactams
Q-Index Code C1
Q-Index Status Confirmed Code
Funding Body We thank L. Goudie for taxonomic identification of marine sponges and acknowledge the generous support of an Australian Development Scholarship (W.B.) and a University of Queensland Scholarship (R.I.). This research was funded in part by the Institute for Molecular Bioscience, the Queensland Brain Institute, The University of Queensland, the National Health and Medical Research Council (project grant #613448) and the Australian Research Council (LP120100088)
Institutional Status UQ

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Created: Thu, 11 Jul 2013, 15:20:50 EST by Debra McMurtrie on behalf of Queensland Brain Institute