Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
Bioorg Med Chem. 2013 Jul 15;21(14):4420-5. doi: 10.1016/j.bmc.2013.04.061. Epub 2013 May 1.
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.
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。
