中文摘要：

目的研究α-芋螺毒素TxIB3个二硫键异构体时大鼠和人类α6／α3β2β3乙酰胆碱受体（nAChRs）的拮抗活性。方法采用Fmoc固相合成法，分别合成TxIB的3个二硫键异构体。利用非洲爪蟾卵母细胞分别表达大鼠和人类的α6／α3β2β3 nAChRs，分别测定3个异构体对它们的拮抗活性。结果成功合成了TxIB的3个二硫键畀构体，并通过超高效液相色谱（UPLC）与基质辅助激光解吸电离飞行时间（MALDI-TOF）质谱进行了鉴定，且为正确。α-芋螺毒素TxIB的3个二硫键异构体在UPLC的洗脱出峰时间差异明显，其亲水性顺序分别为球状异构体（globular）〉带状异构体（ribbon）〉珠子状异构体（bead）。质谱鉴定它们的相对分子质量完全一样，且与理论相对分子质量一致。大鼠与人类α6／α3β2β3 nAChRs在非洲爪蟾卵母细胞中获得了有效表达，并用该技术体系测知了TxIB的3个二硫键异构体的拮抗活性。其中，TxIB的球状异构体活性最强，对大鼠与人类α6／α3β2β3 nAChRs的拮抗活性极其相似，其半抑制浓度（IC50）分别为28．2与32．0 nmol·L-1。而带状异构体和珠子状异构体对大鼠与人类α6／α3β2β3 nAChRs几乎没有拮抗活性，其IC50〉10 μmol·L。结论本实验人工合成的TxIB球状异构体对大鼠与人类α6／α3β2β3 nAChRs具有高选择性强拮抗活性，这为后续TxIB新药研发提供了研究基础。

英文摘要：

OBJECTIVE To investigate antagonistic activities of three isomers of α-conotoxin TxlB on rat and human α6/α3β2β3 nicotinic aeetylcholine receptors （nAChRs）. METHODS Three disulfide bond isomers were synthesized using Fmoc chemistry, which were identified by ultra performance liquid chromatography （UPLC）and confirmed by MALDI-TOF mass spectrometry. Rat and human α6/α3β2β3 nAChRs were expressed in oocytes of Xenopus laevis, which were used to test the antagonistic abilities of the 3 iso- mers. RESULTS The three isomers of α-conotoxin TxIB were synthesized successfully. The retention time of each isomer of α-cono- toxin TxIB was different each other significantly. The observed molecular masses of three isomers were the same, which were consistent with their theoretical molecular mass. Their hydrophilicity orders were globular 〉 ribbon 〉 bead. Both rat and human α6/α3β2β3 nAChRs were expressed in oocytes well. Inhibition of three isomers of α-eonotoxin TxlB on rat and human α6/α3β2β3 nAChRs were evaluated respectively. Among the three isomers of TxIB, the activity of the globular isomer was the most potent one, which had almost same activity at rat and human α6/α3β2β3 nAChRs with corresponding IC50 of 28.2 and 32. 0 nmol · L-1 respectively. However, the other two isomers, ribbon and bead isomers displayed little antagonistic effect on both rat and human α6/α3β2β3 nAChRs only with an ICso of 〉 10 μmol· L-1. CONCLUSION The synthesized globular isomer of α-conotoxin TxlB in this work has a high selectivity and potent antagonistic activity on rat and human α6/α3β2β3 nAChRs, which would be helpful for its new drug development.