Kasheverov Igor E, Shelukhina Irina V, Kudryavtsev Denis S, Makarieva Tatyana N, Spirova Ekaterina N, Guzii Alla G, Stonik Valentin A, Tsetlin Victor I
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Russian Academy of Sciences, Miklukho-Maklaya Street, 16/10, Moscow 117997, Russia.
Elyakov Pacific Institute of Bioorganic Chemistry (PIBOC), Russian Academy of Sciences, Prospect 100 let Vladivostoku, 159, Vladivostok 690022, Russia.
Mar Drugs. 2015 Mar 12;13(3):1255-66. doi: 10.3390/md13031255.
6-Bromohypaphorine (6-BHP) has been isolated from the marine sponges Pachymatisma johnstoni, Aplysina sp., and the tunicate Aplidium conicum, but data on its biological activity were not available. For the nudibranch mollusk Hermissenda crassicornis no endogenous compounds were known, and here we describe the isolation of 6-BHP from this mollusk and its effects on different nicotinic acetylcholine receptors (nAChR). Two-electrode voltage-clamp experiments on the chimeric α7 nAChR (built of chicken α7 ligand-binding and glycine receptor transmembrane domains) or on rat α4β2 nAChR expressed in Xenopus oocytes revealed no action of 6-BHP. However, in radioligand analysis, 6-BHP competed with radioiodinated α-bungarotoxin for binding to human α7 nAChR expressed in GH4C1 cells (IC50 23 ± 1 μM), but showed no competition on muscle-type nAChR from Torpedo californica. In Ca2+-imaging experiments on the human α7 nAChR expressed in the Neuro2a cells, 6-BHP in the presence of PNU120596 behaved as an agonist (EC50 ~80 μM). To the best of our knowledge, 6-BHP is the first low-molecular weight compound from marine source which is an agonist of the nAChR subtype. This may have physiological importance because H. crassicornis, with its simple and tractable nervous system, is a convenient model system for studying the learning and memory processes.
6-溴hypaphorine（6-BHP）已从海洋海绵约翰逊帕奇马蒂斯海绵、阿普利西纳属海绵以及被囊动物圆锥扁海鞘中分离出来，但关于其生物活性的数据尚不可得。对于裸鳃亚目软体动物粗角海兔，此前未知其体内有内源性化合物，在此我们描述了从这种软体动物中分离出6-BHP及其对不同烟碱型乙酰胆碱受体（nAChR）的影响。在非洲爪蟾卵母细胞中表达的嵌合α7 nAChR（由鸡α7配体结合域和甘氨酸受体跨膜域构建）或大鼠α4β2 nAChR上进行的双电极电压钳实验表明，6-BHP没有作用。然而，在放射性配体分析中，6-BHP与放射性碘化α-银环蛇毒素竞争结合在GH4C1细胞中表达的人α7 nAChR（IC50为23±1μM），但对加州电鳐的肌肉型nAChR没有竞争作用。在Neuro2a细胞中表达的人α7 nAChR上进行的Ca2+成像实验中，6-BHP在存在PNU120596的情况下表现为激动剂（EC50约为80μM）。据我们所知，6-BHP是首个来自海洋来源的低分子量化合物，它是nAChR亚型的激动剂。这可能具有生理重要性，因为粗角海兔具有简单且易于处理神经系统，是研究学习和记忆过程的便利模型系统。
