甘草次酸衍生物药效学筛选及相关机制的探讨
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摘要
甘草次酸类衍生物药理学作用十分广泛,开发前景远大。为了保持和增强活性,减少副作用,合成了两个系列新的甘草次酸衍生物。我们从抗炎、镇痛、镇咳、抗菌四方面对这些新化合物进行了活性研究,同时还利用理论方法对其可能的类固醇激素相关机制进行初步探讨。
1.抗炎作用
采用二甲苯致小鼠耳肿、醋酸致小鼠血管通透性增高、角叉菜致大鼠足肿等炎症模型对甘草次酸的抗炎活性进行筛选。甘草次酸衍生物GTA-1、GTA-2、GTA-3、GTA-6、GTA-7、GTA-8、GTA-10、GTA-12、GTA-13、GTA-14、GTA-15、GTA-18在50mg╱kg剂量时对二甲苯致小鼠耳肿有抑制作用。GTA-7、GTA-8、GTA-10、GTA-12、GTA-15在50mg╱kg剂量时均能够明显的抑制醋酸引起的毛细血管通透性的增加。甘草次酸衍生物GTA-2、GTA-3、GTA-4、GTA-5、GTA-6、GTA-8在50mg/kg剂量时能够明显抑制角叉菜所致足肿胀。其中,化合物GTA-2、GTA-3、GTA-6、GTA-8、GTA-10、GTA-12、GTA-15至少在两个模型中均有抑制炎症功效。GTA-2、GTA-3、GTA-8、GTA-15的抗炎作用与同剂量的地塞米松相当,GTA-2的抗炎活性呈剂量依赖性。故本实验的结果表明甘草次酸衍生物具有很强的抗炎活性。
2.镇痛作用
外周镇痛模型中,GTA-2、GTA-4、GTA-8在50mg╱kg剂量时对醋酸引起的小鼠扭体反应均有抑制作用,抑制强度顺序为GTA-2＞GTA-4＞GTA-8,其中GTA-2的抑制强度与等剂量阿司匹林的镇痛作用相当,GTA-2呈现剂量依赖性而在中枢性镇痛模型—热板实验中,该类化合物基本对小鼠舔足时间无影响。故甘草次酸衍生物的镇痛作用环节主要是外周神经。
3.镇咳作用
镇咳实验中,我们采用了氨水引咳和SO2引咳两种动物模型来评价甘草次酸衍生物的活性。GTA-2、GTA-4、GTA-6、GTA-8在50mg/kg剂量时对氨水起的小鼠咳嗽有抑制作用;GTA-1、GTA-2、GTA-3、GTA-4、GTA-5、GTA-6、GTA-8在50mg/kg时对SO2引起的小鼠咳嗽有抑制作用。其中,GTA-2、GTA-4、GTA-6、GTA-8四个化合物在两个模型中均有作用,镇咳作用强度均低于等剂量的对照药可待因,GTA-2在两个动物模型中都呈剂量依赖性。故此类化合物具有一定镇咳作用。
4.抑菌作用
我们还用MIC法筛选甘草次酸类衍生物的抗菌活性。结果表明,化合物的抗菌活性极弱。
5.机制的理论研究
通过比较了甘草次酸类化合物与类固醇激素3D结构,表明它们在结构上具有相似性。我们采用以具有同源性的类固醇激素受体和代谢酶作为受体,以类固醇激素为阳性对照配体,用对接的方法,研究甘草次酸及其预测代谢产物与受体的结合能力。结果表明,甘草次酸和脱氧甘草次酸与受体几乎没有结合能力;与3α-、3β20α-脱氢酶可能存在相互作用;代谢产物与酮基异构酶存在相互作用;甘草次酸衍生物与受体和酶都没有结合能力,提示与其的相关功能无关联。理论研究表明,与甘草次酸相比,甘草次酸衍生物可能与类固醇受体和代谢酶的相关性更小。
综上所述,甘草次酸类化合物具有较强抗炎和外周镇痛活性,还有一定镇咳作用。我们通过理论研究,发现了一些作用规律,但要真正的阐明作用规律。需要大量更深入的理论和实验研究。
Glycyrrhetic acid derivatives possess a wide range of pharmacological properties,and they have tremendous exploitation prospect.To retain and enhance intrinsical activities of glycyrrhetic acid,and to lessen and avoid side effect,we synthesized two series of new glycyrrhetic acid derivatives.Multiple kinds of animal models were used to evaluate its anti-inflammatory,analgesic,antibechic and antibacterial effect.Besides,we carried out preliminary investigation to their mechanism of action by theoretical study.
1.Anti-inflammatory activity
In anti-inflammatory experiments,we used three animal models,respectively mice ear swelling induced by dimethylbenzene,mice capillary permeability induced by acetic acid and rats hind paw swelling induced by carrageenin.Glycyrrhetic acid derivatives—GTA-1,GTA-2,GTA-3,GTA-6,GTA-7,GTA-8,GTA-10,GTA-12, GTA-13,GTA-14,GTA-15,GTA-18 exhibited inhibitory activities on 50mg/kg dose in the model of mice ear edema by dimethylbenzene.GTA-7,GTA-8,GTA-10, GTA-10,GTA-12,GTA-15 can inhibited obviously capillary permeability induced by acetic acid on 50mg/kg dose.In the model of hind paw swelling by carrageenin, GTA-2、GTA-3、GTA-4、GTA-5、GTA-6、GTA-8 showed inhibitory activities on 50mg/kg dose.Among them,GTA-2,GTA-3,GTA-6,GTA-8,GTA-10,GTA-12, GTA-15 exhibited inhibitory effect at least in two inflammation models. Anti-inflammatory intensity of GTA-2,GTA-3,GTA-8,GTA-15 were almost similar to isodose Dexamethasone.Moreover,GTA-2 showed dose dependent on 10,30,100mg/kg.Results in our study showed that glycyrrhetic acid in our study possessed high anti-inflammatory activities.
2.Analgesic activity
In the peripheral analgesic experiment,Compounds GTA-2,GTA-4,GTA-8 exhibited inhibitory activities in the mice writhing test induced by acetic acid on 50mg/kg dose.The inhibitory rate of writhing of GTA-2 resembled with that of isodose Aspirin.Further,GTA-2 presented dose dependent.Howover,GTA derivatives hadn't an influence to licking paw time in hot plate test.So their analgesic effect mainly act on peripheral nerve.
3.Antibechic effect
In preventing cough experiments,we used two animal models—induced by ammonia water and SO_2 to evaluate their activities.Compounds GTA-2,GTA-4,GTA-6,GTA-8(50mg/kg)could inhibit cough in mice induced by ammonia water.GTA-1,GTA-2,GTA-3,GTA-4,GTA-5,GTA-6,GTA-8 all showed antibechic activities in the model of mice cough by SO_2.Among them, GTA-2,GTA-4,GTA-6,GTA-8 exhibited inhibitory action in both models.But the intensity is not so good as isodose Codeine.Therefore,glycyrrhetic acid in our study could prevent coughing,but the intensity is moderate.
4.Antibacterial activity
With Microdilution method,we screened their antibacterial activitiy.Result showed that glycyrrhetic acid derivates in our study had weak or almost no activity.
5.Theoretical study on mechanisms
Comparing the structures of glycyrrhetic acid derivatives with that of steroids, we confirmed their structures were very similar.And then,we investigated the binding capability of glycyrrhetic acid,predicted metabolites and derivatives with receptors and metabolic enzymes related steroids.Results showed there was almost no binding capability between glycyrretic acid,its deoxy-compound and receptors of steroids;And they can act with 3α-,3β-20α- hydroxysteroid dehydogenase;its metabolites can bind with 3-ketosteroid isomerase;Glycyrrhetic acid derivatives had no binding capability with receptors and metabolic enzymes,and it suggested there was no relationship of functions between receptors and metabolic enzymes and glycyrrhetic acid derivatives.Theoretical study showed that glycyrrhetic acid derivatives hadn't closer association with receptors and metabolic enzymes related steroid than glycyrrhetic acid.
In conclusion,glycyrrhetic acid derivatives exhibited powerful lanti-inflammatory action and potent analgesic effect,and they also relieve cough. Besides,we found some potential rules by theoretical study.In order to illustrate the true function mechanism,Further studies should been carried out.
1.抗炎作用
采用二甲苯致小鼠耳肿、醋酸致小鼠血管通透性增高、角叉菜致大鼠足肿等炎症模型对甘草次酸的抗炎活性进行筛选。甘草次酸衍生物GTA-1、GTA-2、GTA-3、GTA-6、GTA-7、GTA-8、GTA-10、GTA-12、GTA-13、GTA-14、GTA-15、GTA-18在50mg╱kg剂量时对二甲苯致小鼠耳肿有抑制作用。GTA-7、GTA-8、GTA-10、GTA-12、GTA-15在50mg╱kg剂量时均能够明显的抑制醋酸引起的毛细血管通透性的增加。甘草次酸衍生物GTA-2、GTA-3、GTA-4、GTA-5、GTA-6、GTA-8在50mg/kg剂量时能够明显抑制角叉菜所致足肿胀。其中,化合物GTA-2、GTA-3、GTA-6、GTA-8、GTA-10、GTA-12、GTA-15至少在两个模型中均有抑制炎症功效。GTA-2、GTA-3、GTA-8、GTA-15的抗炎作用与同剂量的地塞米松相当,GTA-2的抗炎活性呈剂量依赖性。故本实验的结果表明甘草次酸衍生物具有很强的抗炎活性。
2.镇痛作用
外周镇痛模型中,GTA-2、GTA-4、GTA-8在50mg╱kg剂量时对醋酸引起的小鼠扭体反应均有抑制作用,抑制强度顺序为GTA-2＞GTA-4＞GTA-8,其中GTA-2的抑制强度与等剂量阿司匹林的镇痛作用相当,GTA-2呈现剂量依赖性而在中枢性镇痛模型—热板实验中,该类化合物基本对小鼠舔足时间无影响。故甘草次酸衍生物的镇痛作用环节主要是外周神经。
3.镇咳作用
镇咳实验中,我们采用了氨水引咳和SO2引咳两种动物模型来评价甘草次酸衍生物的活性。GTA-2、GTA-4、GTA-6、GTA-8在50mg/kg剂量时对氨水起的小鼠咳嗽有抑制作用;GTA-1、GTA-2、GTA-3、GTA-4、GTA-5、GTA-6、GTA-8在50mg/kg时对SO2引起的小鼠咳嗽有抑制作用。其中,GTA-2、GTA-4、GTA-6、GTA-8四个化合物在两个模型中均有作用,镇咳作用强度均低于等剂量的对照药可待因,GTA-2在两个动物模型中都呈剂量依赖性。故此类化合物具有一定镇咳作用。
4.抑菌作用
我们还用MIC法筛选甘草次酸类衍生物的抗菌活性。结果表明,化合物的抗菌活性极弱。
5.机制的理论研究
通过比较了甘草次酸类化合物与类固醇激素3D结构,表明它们在结构上具有相似性。我们采用以具有同源性的类固醇激素受体和代谢酶作为受体,以类固醇激素为阳性对照配体,用对接的方法,研究甘草次酸及其预测代谢产物与受体的结合能力。结果表明,甘草次酸和脱氧甘草次酸与受体几乎没有结合能力;与3α-、3β20α-脱氢酶可能存在相互作用;代谢产物与酮基异构酶存在相互作用;甘草次酸衍生物与受体和酶都没有结合能力,提示与其的相关功能无关联。理论研究表明,与甘草次酸相比,甘草次酸衍生物可能与类固醇受体和代谢酶的相关性更小。
综上所述,甘草次酸类化合物具有较强抗炎和外周镇痛活性,还有一定镇咳作用。我们通过理论研究,发现了一些作用规律,但要真正的阐明作用规律。需要大量更深入的理论和实验研究。
Glycyrrhetic acid derivatives possess a wide range of pharmacological properties,and they have tremendous exploitation prospect.To retain and enhance intrinsical activities of glycyrrhetic acid,and to lessen and avoid side effect,we synthesized two series of new glycyrrhetic acid derivatives.Multiple kinds of animal models were used to evaluate its anti-inflammatory,analgesic,antibechic and antibacterial effect.Besides,we carried out preliminary investigation to their mechanism of action by theoretical study.
1.Anti-inflammatory activity
In anti-inflammatory experiments,we used three animal models,respectively mice ear swelling induced by dimethylbenzene,mice capillary permeability induced by acetic acid and rats hind paw swelling induced by carrageenin.Glycyrrhetic acid derivatives—GTA-1,GTA-2,GTA-3,GTA-6,GTA-7,GTA-8,GTA-10,GTA-12, GTA-13,GTA-14,GTA-15,GTA-18 exhibited inhibitory activities on 50mg/kg dose in the model of mice ear edema by dimethylbenzene.GTA-7,GTA-8,GTA-10, GTA-10,GTA-12,GTA-15 can inhibited obviously capillary permeability induced by acetic acid on 50mg/kg dose.In the model of hind paw swelling by carrageenin, GTA-2、GTA-3、GTA-4、GTA-5、GTA-6、GTA-8 showed inhibitory activities on 50mg/kg dose.Among them,GTA-2,GTA-3,GTA-6,GTA-8,GTA-10,GTA-12, GTA-15 exhibited inhibitory effect at least in two inflammation models. Anti-inflammatory intensity of GTA-2,GTA-3,GTA-8,GTA-15 were almost similar to isodose Dexamethasone.Moreover,GTA-2 showed dose dependent on 10,30,100mg/kg.Results in our study showed that glycyrrhetic acid in our study possessed high anti-inflammatory activities.
2.Analgesic activity
In the peripheral analgesic experiment,Compounds GTA-2,GTA-4,GTA-8 exhibited inhibitory activities in the mice writhing test induced by acetic acid on 50mg/kg dose.The inhibitory rate of writhing of GTA-2 resembled with that of isodose Aspirin.Further,GTA-2 presented dose dependent.Howover,GTA derivatives hadn't an influence to licking paw time in hot plate test.So their analgesic effect mainly act on peripheral nerve.
3.Antibechic effect
In preventing cough experiments,we used two animal models—induced by ammonia water and SO_2 to evaluate their activities.Compounds GTA-2,GTA-4,GTA-6,GTA-8(50mg/kg)could inhibit cough in mice induced by ammonia water.GTA-1,GTA-2,GTA-3,GTA-4,GTA-5,GTA-6,GTA-8 all showed antibechic activities in the model of mice cough by SO_2.Among them, GTA-2,GTA-4,GTA-6,GTA-8 exhibited inhibitory action in both models.But the intensity is not so good as isodose Codeine.Therefore,glycyrrhetic acid in our study could prevent coughing,but the intensity is moderate.
4.Antibacterial activity
With Microdilution method,we screened their antibacterial activitiy.Result showed that glycyrrhetic acid derivates in our study had weak or almost no activity.
5.Theoretical study on mechanisms
Comparing the structures of glycyrrhetic acid derivatives with that of steroids, we confirmed their structures were very similar.And then,we investigated the binding capability of glycyrrhetic acid,predicted metabolites and derivatives with receptors and metabolic enzymes related steroids.Results showed there was almost no binding capability between glycyrretic acid,its deoxy-compound and receptors of steroids;And they can act with 3α-,3β-20α- hydroxysteroid dehydogenase;its metabolites can bind with 3-ketosteroid isomerase;Glycyrrhetic acid derivatives had no binding capability with receptors and metabolic enzymes,and it suggested there was no relationship of functions between receptors and metabolic enzymes and glycyrrhetic acid derivatives.Theoretical study showed that glycyrrhetic acid derivatives hadn't closer association with receptors and metabolic enzymes related steroid than glycyrrhetic acid.
In conclusion,glycyrrhetic acid derivatives exhibited powerful lanti-inflammatory action and potent analgesic effect,and they also relieve cough. Besides,we found some potential rules by theoretical study.In order to illustrate the true function mechanism,Further studies should been carried out.
引文
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