Studies On Pharmacodynamics And Mechanisms Of Glycyrrhetic Acid Derivatives

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 activityIn 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 activityIn 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 effectIn preventing cough experiments,we used two animal models—induced by ammonia water and SO₂ 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 SO₂.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 activityWith 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 mechanismsComparing 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.