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 journalArticleResearchpeer-review

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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Sesterterpenes
Glycine Receptors
Lactams
Porifera
glycine
Modulators
modulators
sulfates
electrophysiology
pharmacology
acetylation
bioassay
clamps
metabolites
fractionation
acetates
chlorides
disorders
Sulfates
probes

Cite this

Islam, Md ; Balansa, Walter ; Fontaine, Frank ; Piggott, Andrew M ; Zhang, Hua ; Xiao, Xue ; Webb, Timothy I. ; Gilbert, Daniel F ; Lynch, Joseph W ; Capon, Robert J. / Sesterterpene glycinyl-lactams : A new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia. In: Organic & Biomolecular Chemistry. 2013 ; Vol. 11, No. 28. pp. 4695-4701.
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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 biosyntheticallyrelated 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.",
author = "Md Islam and Walter Balansa and Frank Fontaine and Piggott, {Andrew M} and Hua Zhang and Xue Xiao and Webb, {Timothy I.} and Gilbert, {Daniel F} and Lynch, {Joseph W} and Capon, {Robert J}",
year = "2013",
doi = "10.1039/C3OB40861B",
language = "English",
volume = "11",
pages = "4695--4701",
journal = "Organic & Biomolecular Chemistry",
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}

Islam, M, Balansa, W, Fontaine, F, Piggott, AM, Zhang, H, Xiao, X, Webb, TI, Gilbert, DF, Lynch, JW & Capon, RJ 2013, 'Sesterterpene glycinyl-lactams: A new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia', Organic & Biomolecular Chemistry, vol. 11, no. 28, pp. 4695-4701. https://doi.org/10.1039/C3OB40861B

Sesterterpene glycinyl-lactams : A new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia. / Islam, Md; Balansa, Walter; Fontaine, Frank ; Piggott, Andrew M; Zhang, Hua; Xiao, Xue ; Webb, Timothy I.; Gilbert, Daniel F; Lynch, Joseph W; Capon, Robert J.

In: Organic & Biomolecular Chemistry, Vol. 11, No. 28, 2013, p. 4695-4701.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Sesterterpene glycinyl-lactams

T2 - A new class of glycine receptor modulator from Australian marine sponges of the genus Psammocinia

AU - Islam, Md

AU - Balansa, Walter

AU - Fontaine, Frank

AU - Piggott, Andrew M

AU - Zhang, Hua

AU - Xiao, Xue

AU - Webb, Timothy I.

AU - Gilbert, Daniel F

AU - Lynch, Joseph W

AU - Capon, Robert J

PY - 2013

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N2 - 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 biosyntheticallyrelated 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.

AB - 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 biosyntheticallyrelated 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.

U2 - 10.1039/C3OB40861B

DO - 10.1039/C3OB40861B

M3 - Article

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EP - 4701

JO - Organic & Biomolecular Chemistry

JF - Organic & Biomolecular Chemistry

SN - 1477-0520

IS - 28

ER -