Derivation Of L-menthol And Its Antidepressant-like Activity,Anticonvulsant Activity And Hypnotic Activities

Mint?Menthahaplocalyx?,Labiatae,Mentha,perennial root herb,is also known as Herb Menthae.The whole plant can be used as medicine,cool-natured,acrid flavour,in to the lungs and liver meridians,has the effect of manage hepaticqi,removing kidney qi,refreshing the mind.Mint contains a variety of terpenoids,flavonoids,organic acids composition,among which,L-menthol?LM?is the main active ingredient in mint.L-menthol has the effects of anti-bacterial,analgesic,anti-tumor,promote penetration,kill mosquitoes,and improve memory,etc.The chemical structure of L-menthol is very simple and clear.And it was monoterpenoid natural product.The main ring contains a phenolic hydroxyl group,which is easy to synthesize and has good reactivity.Depression,Convulsions,Pathogenesis is closely related to the yin and yang imbalance in blood in the organs and liver controlling dispersion abnormal.Mint has the effect of soothing the liver and relieving depression,tranquilizing and allaying excitement.L-menthol may be the main material basis of mint to play a role in soothing liver and treatment of depression.To find a new type of antidepressant drugs,anticonvulsant drugs,hypnotic drugs,L-menthol was derivatized and its antidepressant,anticonvulsant,and hypnotic activities were screened for its derivatives in this experiment.Research methods and results are summarized as follows:?1?Synthesis of L-menthol derivative:In this experiment,17 kinds of compounds were synthesized by esterification reaction between L-menthol and organic acids in the presence of dehydrating agent EDCI and catalyst DMAP.The chemical structure was confirmed by ¹H-NMR and ¹³C-NMR analyses.?2?L-menthol derivatives antidepressant activity screened:The forced swimming test?FST?was used to screen the antidepressant activities of L-menthol and its derivatives.Experimental study found that L-menthol has an antidepressant effect,L-menthol derivative benzoate,3-furoformate,2-naphthoate,furoate,oleate,linoleate,?-lipoic acid esters,malonic acid esters,sorbate,succinate?256?mol/kg?showed varying degrees of antidepressant activity,Among them,menthyl benzoate?LM1?had the best antidepressant effect,Its sub-effective dose?6.4?mol/kg?combined with Fluoxetine?5 mg/kg,i.p.?,tianeptine?15 mg/kg,i.p.?and reboxetine?2.5 mg/kg,i.p.?can significantly shorten the immobility time of mice.LM1 significantly reduced FST immobility at an effective dose of 192?mol/kg.Using bicuculline?a competitive?-aminobutyric acid antagonist,4 mg/kg,i.p.?,N-Methyl-D-aspartic acid?NMDA,glutamate agonist,75 mg/kg,i.p.?,ondansetron?a highly selective 5-HT₃ receptor antagonist,8 mg/kg,i.p?and haloperidol?Non-selective D₂ receptor antagonist,0.2mg/kg,i.p.?significantly reversed the antidepressant effect of LM1?192?mol/kg,i.g.?.The results showd that LM1 exerted antidepressant effects by acting on glutamatergic,?-aminobutyric acid,serotonergic and dopaminergic nervous systems.?3?L-menthol derivatives anticonvulsant activity screened:Anticonvulsant screened of L-menthol and its derivatives were screened with pentylenetetrazol-induced mouse convulsive model.Results L-menthol showed some anticonvulsant effects.The anticonvulsant activity of benzoate,?-lipoic acid ester and 2-naphthoate were stronger than that of L-menthol.And 2-naphthoate had the most significant anticonvulsant effect.Further three dose groups of 2-naphthoic acid ester,high?512?mol/kg?,medium?256?mol/kg?,low?64?mol/kg?,were set.The anticonvulsant activity of2-naphthoic acid ester was further studied with pentylenetetrazol and N-methyl-D-aspartate induced mouse convulsion model respectively.The results showed that 2-naphthoate high dose?512?mol/kg?and medium dose?256?mol/kg?could reverse the GABA content induced by pentylenetetrazol NMDA leads to the increase of glutamate content,effectively inhibiting the occurrence of convulsions,shortening the duration of convulsions and decreasing the convulsion mortality.?4?L-menthol derivatives hypnotic activity screened.Screening of the hypnotic activity of L-menthol derivatives by used Z-Z mouse autonomous activity instrument to record the number of autonomous activities of mice after administration.The results showd that naphthenic acid esters had a significant inhibitory effect on the autonomous activities of mice among L-menthol derivatives.The naphthenic acid ester sub-dose?64?mol/kg?combined with 5-HTP can significantly shortened sleep latency and prolonged sleeping time caused by pentobarbital sodium.And its effective dose?320?mol/kg?could antagonize the central stimulant effect of thiosemicarbazide,promote sleep and improve sleep quality.