Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator
Australian marine sponge alkaloids as a new class of glycine-gated chloride channel receptor modulator
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DOI：
10.1016/j.bmc.2013.04.061
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发表时间：
2013-07-15
影响因子：
3.5
通讯作者：
Capon, Robert J.
中科院分区：
文献类型：
--
作者：
Balansa, Walter;Islam, Robiul;Capon, Robert J.
海绵兰氏藻的化学分析。flabelliformis返回了两种新的倍半萜甘氨酰内酰胺，ianthellalactams A（1）和B（2），已知的海绵倍半萜dictyodendrillin（3）及其乙醇分解产物乙基dictyodendrillin（4），和五种已知的海绵吲哚生物碱，aplysinopsin（5），8 E-3 ′-脱亚氨基-3 ′-氧代aplysinopsin（6），8 Z-3 ′-脱亚氨基-3 ′-氧代aplysinopsin（7），二氢aplysinopsin（8）和tubastrindole B（9）。平衡的混合物6/7显示甘氨酸门控氯离子通道受体（GlyR）拮抗剂活性，与α 1 GlyR相比偏向α 3，而tubastrindole B（9）显示与α 3 GlyR相比偏向α 1。在低至亚微摩尔浓度下，9也是α 1 GlyR的选择性增效剂，对α 3 GlyR没有影响，α 3 GlyR是一种药理学，可证明可用于治疗运动障碍，如痉挛和过度兴奋。我们的调查1-9的GlyR调节性能的进一步支持了一些结构相关的吲哚生物碱的合成。(C)2013爱思唯尔有限公司保留所有权利。
Chemical analysis of a specimen of the sponge lanthella 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 alpha 3 over alpha 1 GlyR, while tubastrindole B (9) exhibited a bias towards alpha 1 over alpha 3 GlyR. At low- to sub-micromolar concentrations, 9 was also a selective potentiator of alpha 1 GlyR, with no effect on alpha 3 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. (C) 2013 Elsevier Ltd. All rights reserved.