澳大利亚海洋海绵生物碱作为一类新型甘氨酸门控氯离子通道受体调节剂。

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

机构信息

Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.

出版信息

Bioorg Med Chem. 2013 Jul 15;21(14):4420-5. doi: 10.1016/j.bmc.2013.04.061. Epub 2013 May 1.

DOI:10.1016/j.bmc.2013.04.061

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.

摘要

对标本 Ianthella cf. flabelliformis 的化学分析返回了两种新的倍半萜糖基内酰胺，即 ianthellalactams A（1）和 B（2），已知的海绵倍半萜二萜醇（3）及其乙醇解产物乙基二萜醇（4），以及五种已知的海绵吲哚生物碱，aplysinopsin（5），8E-3'-去亚氨基-3'-氧代aplysinopsin（6），8Z-3'-去亚氨基-3'-氧代aplysinopsin（7），二氢aplysinopsin（8）和 tubastrindole B（9）。平衡混合物 6/7 表现出甘氨酸门控氯离子通道受体（GlyR）拮抗剂活性，对 α3 GlyR 的偏向大于 α1 GlyR，而 tubastrindole B（9）对 α1 GlyR 的偏向大于 α3 GlyR。在低至亚微摩尔浓度下，9 也是 α1 GlyR 的选择性增强剂，对 α3 GlyR 没有影响——这种药理学在治疗运动障碍（如痉挛和hyperekplexia）方面可能很有用。我们对 1-9 的 GlyR 调节特性的研究还得到了许多结构相关的吲哚生物碱的合成的支持。