摘要
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 1.8,3.6,5.4μmol·L-1,Aom0498-3 1.8,3.6,5.4μmol·L-1以及舒格麻坦(sugammadex)1.8,3.6,5.4μmol·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5.4μmol·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5.4μmol·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5.4μmol·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。
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-r- cyclodextrin derivatives, Aom0498-1 and Aom0498-3, were synthesized using one-pot reaction. ① r-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 r-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.③Rabbits were iv administered with r-cyclodextrin, Aom0498-1, Aom0498-3 and sugammadex 6 mg· kg-1 accordingly after paralysis and recovery time of the ear pinch reflex was recorded. ④Aom0498-1 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 ixmol· L-1 groups [ （2.5± 1.0） %, （6.9 ± 2.6） % and （24.5 ± 9.1 ） % 3 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 r-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 sugam- madex 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 r-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 -/-cyclodextrin 2 mg-kg-1 group, and the recov- ery time of the train-of-four ratio to 75% in Aom0498-1 2 mg·kg-1 group was significantly longer than that in sug- ammadex 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 r-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 r-cyclodextrin derivatives might be served as potential candidates of selective muscle-relaxant antagonists.
出处
《中国药理学与毒理学杂志》
CAS
CSCD
北大核心
2012年第6期787-793,共7页
Chinese Journal of Pharmacology and Toxicology
基金
The project supported by National Major Scientific and Technological Special Project for "Significant New Drugs Development" Funds(2012ZX09103101-012)
National Innovation Fund(12C26213302758)
Scienceand Technology Major Project Funds(2012C03SA150009)~~
