Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
Org Biomol Chem. 2013 Jul 28;11(28):4695-701. doi: 10.1039/c3ob40861b. Epub 2013 Jun 11.
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.
生物测定指导的三种产自澳大利亚南部海域的海绵 Psammocinia 属化合物的分段分离，这些海绵因能够调节甘氨酸门控氯离子通道受体 (GlyRs) 而被选中，得到了罕见的海洋甾体 (-)-ircinianin (1) 和 (-)-ircinianin 硫酸盐 (2)，以及新的生物合成相关代谢物 (-)-ircinianin 内酰胺 A (3)、(-)-ircinianin 内酰胺 A 硫酸盐 (4)、(-)-oxoircinianin (5)、(-)-oxoircinianin 内酰胺 A (6) 和 (-)-ircinianin 内酯 A (7)。1 的乙酰化产物为 (-)-ircinianin 乙酸酯 (8)。对化合物 1-8 进行全细胞贴附式膜片钳电生理学研究，确定了 3 是一种非常有效和选择性的α3 GlyR 增强剂，6 是一种选择性的α1 GlyR 增强剂。甾体化合物 1-8 的发现和特征描述，特别是甘氨酰内酰胺 3 和 6，为 GlyR 药理学提供了有价值的新见解。这些见解有可能为研究 GlyR 分布和功能的新分子工具的开发以及治疗广泛的 GlyR 介导的疾病和障碍提供信息和启发。
