title: Sesterterpene glycinyl-lactams: a new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia.
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.
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: Frank
authors.initials: F
authors.lastname: Fontaine
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Piggott
authors.forename: Hua
authors.initials: H
authors.lastname: Zhang
authors.forename: Xue
authors.initials: X
authors.lastname: Xiao
authors.forename: Timothy I
authors.initials: TI
authors.lastname: Webb
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gilbert
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Lynch
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Capon
mesh_terms: D000818:Animals; D059001:Aquatic Organisms / Q000737:chemistry*; D001688:Biological Products / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology; D005998:Glycine / Q000737:chemistry*; D057809:HEK293 Cells; D006801:Humans; D007769:Lactams / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology*; D011161:Porifera / Q000737:chemistry*; D018009:Receptors, Glycine / Q000378:metabolism*; D054830:Sesterterpenes / Q000737:chemistry*
chemical_list: D001688:Biological Products; D007769:Lactams; D018009:Receptors, Glycine; D054830:Sesterterpenes; D005998:Glycine