title: Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator.
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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
authors.forename: Walter
authors.initials: W
authors.lastname: Balansa
authors.forename: Robiul
authors.initials: R
authors.lastname: Islam
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gilbert
authors.forename: Frank
authors.initials: F
authors.lastname: Fontaine
authors.forename: Xue
authors.initials: X
authors.lastname: Xiao
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Piggott
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lynch
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Capon
mesh_terms: D000470:Alkaloids / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001315:Australia; D018118:Chloride Channels / Q000037:antagonists & inhibitors* / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D011161:Porifera / Q000737:chemistry*; D011485:Protein Binding / Q000187:drug effects; D018009:Receptors, Glycine / Q000737:chemistry / Q000378:metabolism*
chemical_list: D000470:Alkaloids; D018118:Chloride Channels; D018009:Receptors, Glycine