Inhibitory effects of lappaconitine on the neuronal isoforms of voltage-gated sodium channels  

作　　者：Yan-fen Li Yue-ming Zheng Yong Yu Yong Gan Zhao-bing Gao 

机构地区：[1]Shanghai Key Laboratory of Bio-Energy Crops, School of Life Sciences, Shanghai University, Shanghai 200444, China [2]CAS Key Laboratory of Receptor Research, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China [3]University of Chinese Academy of Sciences, Beijing 100049, China [4]Department of Neurosurgery, Zhongshan Hospital, Fudan University, Shanghai 200032, China

出　　处：《Acta Pharmacologica Sinica》2019年第4期451-459,共9页中国药理学报（英文版）

基　　金：Personalized Medicines "Molecular Signature-Based Drug Discovery and Development"(Strategic Priority Research Program of the Chinese Academy of Sciences, Grant No. XDA12040221 and XDA15050308);the National Natural Science Foundation of China (81603096, 81773707, 61327014, and 61433017),;the Shanghai Science and Technology Innovation Fund 15431901500.

摘　　要：Lappac on itine (LA) has bee n widely used for postoperative and can cer pain control. LA exhibits excellent an algesic activity with a Ion ger effective time tha n comm on local an esthetics such as tetracai ne and bupivacai ne. However, the mecha nisms un derlyi ng the featured analgesic activity of LA remain largely unknown. Here, we report that LA is an inhibitor of voltage-gated sodium channel 1.7 (Navi.7) stably expressed in human embryonic kidney (HEK293) cells. LA inhibited Navi.7 in a voltage-dependent manner with an IC50 value (with 95% confidence limits) of 27.67 (15.68-39.66) pmol/L when the cell was clamped at -70 mV. In comparison with the quick and reversible inhibition of Navi .7 by tetracaine and bupivacaine, the inhibitory effect of LA was rather slow and irreversible. It took more tha n 10 min to achieve steady-state in hibition when LA (300 pmol/L) was admi nistered. Un like tetracai ne and bupivacai n 巳 LA affected neither the voltage-depende nt activati on nor the in activation of the cha nn els. Five residues in domai n III and domain IV have been reported to be critical for the effects of the two local anesthetics on Nav channels. But our mutant study revealed that only two residues (F1737, N1742) located in domain IV were necessary for the inhibitory activity of LA. The slow onset, irreversibility, and lack of influe nee on cha nnel activati on and in activati on accompa nied with the differe nt molecular determi nants suggest that LA may in hibit Nav1.7 cha nnels in a manner differe nt from local an esthetics. These results may help to un dersta nd the featured an algesic activity of LA, thus ben efiti ng its applicatio n in the clinic and future drug developme nt.

关 键 词：VOLTAGE-GATED sodium channel 1.7 ANALGESICS LAPPACONITINE TETRACAINE BUPIVACAINE 

分 类 号：R[医药卫生]