Design,Synthesis And Evaluation Of The Antiepileptic Activities Of α-asary-laldehyde And Its Derivatives

Considering the different drug development methodologies for Western medicine and TCM, we studied the basis of the complex components in TCM by using dimensionality reduction method. On the principle of "Jun-Shi" inedical pair, "Jun-Shi" compounds, "Jun-Chen-Zuo-Shi" compounds and the guidance of the combination of TCM chemistry, this dissertation were studied the main components of polygala-shichangpu drug compatibility and selected the bioactive ingredients as the parent nucleus. Based on the aforementioned bioactive ingredients, α-asary-laldehyde and its derivatives were designed, synthesized and evaluated. Theoretically, through the whole concept of Prescription-syndrome and herbal composition, the designation could achieve the microcosmic of Western medicine and the integrity of TCM. Meanwhile, this method could provide an important insight into the modernization of TCM and drug design. Three chapters are divided in this dissertation and the main research contents are as follows:1. The overseas and domestic research status of epilepsy treatment were summarized. On the principle of the combination of TCM chemistry, the polygala-shichangpu drug compatibility was selected as the research object.2. Based on the the guidance of "Combination of Traditional Chinese Medicine chemistry", α-asary-laldehyde and its derivatives were designed, synthesized and evaluated through α-asarone which was selected as the bioactive ingredients. The aforementioned components which derived from shichangpu possessing the effects of antitussive, expectorant, antiasthmatic, calmative, spasmolytic and anticonvulsant. Twelve α-asary-laldehyde ester derivatives were designed and synthesized through 3,4,5-trimethoxycinnamic acid and p-methoxycinnamic acid which derived from Poly gala tenuifolia with the effects of calmative, sedative and antiarrhythmic, and a variety of linear chain and branched chain fatty acids, different organic acids substituted on the benzene rings by esterification reaction. Their structures were identified by MS,1H NMR and 13C NMR, and they were not reported in literatures.3. The antiepileptic activities of α-asary-laldehyde were evaluated by the antiepileptic drug development program implemented by the USA National Institutes of Health(NIH). The maximum electroshock seizure test(MES) and rotarod test were used to evaluate the antiepileptic activity and neurotoxicity of α-asary-laldehyde. The median effective dose was 65.4 mg/Kg, the median toxic dose was 692.8 mg/Kg and the protection index(PI) was 10.6. The results showed that α-asary-laldehyde had good antiepileptic activities.Two kinds of classical chemical models induced by pentylenetetrazole and 3-mercaptopropionic acid were selected to investigate the broad spectrum antiepileptic activity and the possible mechanism. The results showed that α-asary-laldehyde could significantly prolong the clonic seizures, inhibit the tonic seizures and reduce mortality, which indicated that a-asary-laldehyde had the broad-spectrum antiepileptic activity. In view of the reasons of seizures induced by aboved two kinds of classical chemical models, we speculated that the α-asary-laldehyde exerted antiepileptic activity by enhacing GABA neurotransmitter levels or modulating the GABA activity.