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

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• 作者：Walter Balansa^a ; ^&dagger ; ; Robiul Islam^b ; ^&dagger ; ; Daniel F. Gilbert^b ; Frank Fontaine^a ; Xue Xiao^a ; Hua Zhang^a ; Andrew M. Piggott^a ; Joseph W. Lynch^b ; ^c ; ^{j.lynch@uq.edu.au} ; Robert J. Capon^a ; ^{r.capon@uq.edu.au}
• 关键词：Glycine-gated chloride channel receptor modulators ; Sesterterpene tetronic acid glycinyl lactams ; Ianthella cf. flabelliformis ; Marine natural products chemistry
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2013
• 出版时间：15 July, 2013
• 年：2013
• 卷：21
• 期：14
• 页码：4420-4425
• 全文大小：470 K

文摘

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¡ä-deimino-3¡ä-oxoaplysinopsin (6), 8Z-3¡ä-deimino-3¡ä-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 ¦Á3 over ¦Á1 GlyR, while tubastrindole B (9) exhibited a bias towards ¦Á1 over ¦Á3 GlyR. At low- to sub-micromolar concentrations, 9 was also a selective potentiator of ¦Á1 GlyR, with no effect on ¦Á3 GlyR¡ªa 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.