OBJECTIVE To explore and screen the candidates of the selective muscle-relaxant antagonist against amino-steroid nondepolarizing muscle relaxants.METHODS Two 6-deoxy-6-thioether-acetylglycine-γ-cyclodextrin derivatives,Aom0498-1 and Aom0498-3,were synthesized using one-pot reaction.① γ-Cyclodextrin,Aom0498-1,Aom0498-3 and sugammadex 1.8,3.6 and 5.4 μmol· L-1 were added to phrenic-nerve-diaphragm preparation of mice accordingly and the reversal rate of muscle contraction was recorded.② Guinea pigs were iv administered with γ-cyclodextrin,Aom0498-1,Aom0498-3 and sugammadex 2 mg· kg-1 accordingly and recovery time of train-of-four ratio to 50％ and 75％ was recorded.③ Rabbits were iv administered with γ-cyclodextrin,Aom0498-1,Aom0498-3 and sugammadex 6 mg· kg-1 accordingly after paralysis and recovery time of the ear pinch reflex was recorded.④ Aom0498-1 and Aom0498-3 2,4 and 8 g·kg-1 were iv given once time accordingly and clinical signs were monitored.RESULTS ① In mouse phrenic-nerve-diaphragm preparation model,the reversal rates of muscle contraction in Aom0498-1 1.8,3.6 and 5.4 μmol· L-1 groups [(2.5 ± 1.0) ％,(6.9 ± 2.6) ％and (24.5 ± 9.1) ％] and those in Aom0498-3 groups [(17.4 ± 1.7) ％,(65.5 ± 0.6) ％ and (100 ± 8.9) ％]were significantly higher than those in the corresponding groups of γ-cyclodextrin [(1.1 ± 0.5)％,(2.6 ±0.7)％,and (10.3 ± 6.1)％] (P ＜0.05).The reversal rates of muscle contraction in Aom0498-3 1.8,3.6 and 5.4 μmol· L-1 groups were significantly higher than those in sugammadex groups.The reversal rates of muscle contraction in Aom0498-1 1.8,3.6 and 5.4 μmol· L-1 groups were significantly lower than those in sugammadex groups.② In the guinea pig model,the time for recovery of the train-of-four ratio to 50％ and 75％ in Aom0498-3 2 mg· kg-1 group was significantly shorter than that in γ-cyclodextrin 2 mg· kg-1 group (P ＜ 0.05),and was equivalent to that in sugammadex 2 mg· kg-1 group.The recovery time of the train-of-four ratio to 50％ in Aom0498-1 2 mg· kg-1 group was significantly shorter than that in γ-cyclodextrin 2 mg·kg-1 group,and the recovery time of the train-of-four ratio to 75％ in Aom0498-1 2 mg·kg-1 group was significantly longer than that in sugammadex 2 mg· kg-1 group.③ In the rabbit model,the recovery time in Aom0498-1 6 mg· kg-1 group and in Aom0498-3 6 mg· kg-1 group was significantly shorter than that in γ-cyclodextrin 6 mg· kg-1 group (P ＜ 0.05).And the recovery time in Aom0498-3 6 mg·kg-1 group was significantly shorter than that in sugammadex 6 mg·kg-1 group.The results of single dose toxicity test showed that more mice in sugammadex 2,4 and 8 g·kg-1 groups with transient to mild side effects were observed when compared with those in the corresponding dose groups of Aom0498-1 or Aom0498-3.CONCLUSION The synthesized Aom0498-1 and Ao0498-3 are of high reversal activities against sugammadex,indicating that the series of γ-cyclodextrin derivatives might be served as potential candidates of selective muscle-relaxant antagonists.%目的 寻找并筛选可选择性地逆转甾类非去极化肌松药的肌松拮抗剂.方法 应用一锅法合成了2种6-脱氧-6-硫醚乙酰基甘氨酸-γ-环糊精衍生物Aom0498-1和Aom0498-3.采用3种动物模型测定Aom0498-1和Aom0498-3对罗库溴铵导致的神经-肌肉阻滞的逆转作用:①小鼠体外神经-膈肌标本模型中的肌张力恢复比率.将小鼠随机分成5组:生理盐水(正常对照组),γ-环糊精1.8,3.6,5.4μmol· L-1,Aom0498-1 1.8,3.6,5.4 μmol·L-1,Aom0498-3 1.8,3.6,5.4 μmol·L-1以及舒格麻坦(sugammadex) 1.8,3.6,5.4 μmol·L-1(阳性对照)组;②豚鼠体内模型中的4个成串刺激比恢复50％及75％的时间.将豚鼠随机分为5组:生理盐水(正常对照),γ-环糊精2 mg·kg-1,Aom0498-1 2 mg· kg-1,Aom0498-3 2 mg· kg-1以及舒格麻坦2 mg· kg-1(阳性对照)组;③家兔体内模型中的捏耳反射恢复时间.将动物随机分为5组:生理盐水(正常对照组),γ-环糊精6 mg·kg-1,Aom0498-1 6 mg·kg-1,Aom0498-3 6 mg· kg-1以及舒格麻坦6 mg·kg-1(阳性对照)组.同时,对Aom0498-1以及Aom0498-3的单次给药毒性也进行了初步的检测,并与舒格麻坦进行了比较.将小鼠随机分为生理盐水组,Aom0498-1 2,4和8 g·kg-1组,Aom0498-3 2,4和8 g·kg-1组以及舒格麻坦2,4和8 g·kg-1组.结果 ①在小鼠神经-膈肌标本模型中,Aom0498-1 1.8,3.6和5.4 μmol·L-1组肌张力恢复比例分别为(2.5±1.0)％,(6.9±2.6)％和(24.5±9.1)％,同浓度Aom0498-3组分别为(17.4±1.7)％,(65.5±0.6)％及(100.0±8.9)％,均显著高于同浓度γ-环糊精组的(1.1±0.5)％,(2.6±0.7)％和(10.3±6.1)％(P＜0.05).Aom0498-3 1.8,3.6和5.4 μmol· L-1组肌张力恢复比例显著高于相应同浓度的舒格麻坦组(P＜0.05),Aom0498-1 1.8,3.6和5.4 μmol L-1组肌张力恢复比例则显著低于相同浓度的舒格麻坦组(P＜0.05).②在豚鼠模型中,Aom0498-3 2 mg· kg-1组4个成串刺激比恢复至50％及75％的时间显著低于γ-环糊精2 mg· kg-1组(P＜0.05),与舒格麻坦2 mg· kg-1组相当;Aom0498-1 2 mg· kg-1组恢复至50％时间显著低于γ-环糊精2 mg· kg-1组,Aom0498-1 2 mg·kg-1组恢复至75％时间显著高于舒格麻坦2 mg· kg-1组.③在家兔模型中,Aom0498-1 6 mg·kg-1组和Aom0498-36 mg· kg-1组恢复时间显著低于γ-环糊精6 mg· kg-1组(P＜0.05).Aom0498-3 6 mg·kg-1组恢复时间显著低于舒格麻坦6 mg· kg-1组.单次给药毒性检测结果显示,舒格麻坦2,4及8 g·kg-1组中出现一过性或中等程度副作用的小鼠数多于Aom0498-1以及Aom0498-3对应浓度组.结论 合成的Aom0498-1和Aom0498-3具有较高的逆转罗库溴铵活性的作用,提示该系列γ-环糊精衍生物可作为候选药物用于选择性肌松拮抗剂的开发.
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