Steroidal Ammonium Compounds as New Neuromuscular Blocking Agents
Steroidal Ammonium Compounds as New Neuromuscular Blocking Agents
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DOI：
10.1111/cbdd.12711
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发表时间：
2016-05
影响因子：
3
通讯作者：
Zhigang Rao;Hao Hu;Jiazhi Tang;Z. Liu;Yue Yang;G. Qiu;Yuling Xiao;Peng Liu;Xianming Hu;X. Zhou;Xuechuan Hong
中科院分区：
文献类型：
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作者：
Zhigang Rao;Hao Hu;Jiazhi Tang;Z. Liu;Yue Yang;G. Qiu;Yuling Xiao;Peng Liu;Xianming Hu;X. Zhou;Xuechuan Hong
神经肌肉阻滞剂是一种广泛应用于外科手术的麻醉辅助剂，它通过阻断神经肌肉接头处的信号传递而引起骨骼肌的松弛。近几十年来，研制了许多神经肌肉阻滞剂，但由于各种原因，没有一种能完全满足临床需要。本研究合成了一系列季铵甾体类神经肌肉阻滞剂，并在离体小鼠膈神经-半膈上评价了它们的生物活性。单季铵和双季铵化合物的初始分离在常规硅胶色谱上非常具有挑战性。因此，最终得到了一种简便的纯化方法，即用溴化钠甲醇溶液预处理硅胶。化合物3g（0.36 μm）和4g（0.37 μm）具有较好的神经肌肉阻滞活性，比罗库溴铵（2.50 μm）的作用强6 ~ 7倍。此外，其他双季铵化化合物也显示出与罗库溴铵接近的良好效力。初步阐明了该系列化合物的构效关系。苄基被认为是一个很有前途的季铵化基团。
Neuromuscular blocking agents are widely used as an anesthesia auxiliary in surgery, which induce relaxation of skeletal muscles by blocking signal transmission at the neuromuscular junction. Many neuromuscular blocking agents s were developed over the past decades, but none of them fully meets the needs of the clinic by various reasons. In this study, a series of quaternary ammonium steroidal neuromuscular blocking agents were synthesized and evaluated on isolated mouse phrenic nerve–hemidiaphragms for their bioactivities. The initial separation of mono‐ and bis‐quaternary ammonium compounds turned out to be very challenging on regular silica gel chromatography. Therefore, a facile purification method, in which the silica gel was pretreated with methanolic sodium bromide solution, was finally achieved. Compounds 3g (0.36 μm) and 4g (0.37 μm) exhibited excellent neuromuscular blocking activities, which were about sixfold to sevenfold higher in potency than that of rocuronium (2.50 μm). In addition, other bis‐quaternized compounds also showed good potencies close to that of rocuronium. Furthermore, the preliminary structure–activity relationship of this series was also elucidated. Benzyl group was found to be a promising quaternary group in this series.