Survey Investigation of Lead Compounds Towards Cerebral Insufficiency Improving Activity

1.β-卡宾类化合物的合成：以N-羟色胺和胱氨酸为原料，合成了多种海洋β-卡宾生物碱类化合物。以1-甲氧基甲基β-咔啉和氮杂环十一烯为原料，首次完成了海洋β-咔啉生物碱--曼扎明C的全合成。合成了甘露糖胺A的中心环系--吡咯异喹啉。在这些合成过程中合成了40多个β-咔啉衍生物，并进行了筛选试验。研究了3，4-二氢-β-咔啉的烷基化反应和不对称还原反应。研究了Pictet-Spengler与Lewis酸和手性Lewis酸的反应。还完成了部分海洋神经酰胺的全合成。2.真菌抗中枢神经系统活性成分的研究概况：1)体外测定真菌和地衣的单胺氧化酶抑制活性。用…法测定了金针菇去甲酸和霉菌TL-1的MAOI活性更多关于体内抗利血平作用的研究。2)通过大鼠血管平滑肌实验筛选降压活性成分，考察了婆罗洲几种民间药物的抗内皮素1(或去甲肾上腺素)活性。3)从担子菌中分离得到HS-A、-B和-C，作为类似罂粟碱的松弛小鼠小肠的活性成分。3.脑功能不全改善活动的药理学评价：为了筛选和评价β-卡波林改善脑功能不全的活性，进行了几个药理研究：1)胆囊素(CKK)相关活性，2)钙拮抗活性，3)增强胆碱能作用和4)GABA相关活性。在分离的制剂中，一些β-Caroline对CCK有特异的拮抗作用，另一些则具有血管扩张作用，可能与钙拮抗作用有关。大多数具有CCK拮抗作用的化合物在体外也能阻断CCK诱导的运动抑制。这些化合物可能是最有希望作为治疗应用的先导化合物。除上述试验外，还进行了一些研究以阐明药物作用的中枢机制。较少

1. Synthesis of beta-carbolines : Various eudistomins, marine beta-carboline alkaloids, were synthesized from N-hydroxytryptamine and cystine derivatives. First total synthesis of manzamine C, marine beta-carboline alkaloid, was completed from 1-methoxycarbonylmethyl-beta-carboline and azacycloundecene. The central ring system of manzamine A, pyrroloisoquinoline, was also synthesized. Over 40 compounds of beta-carboline derivatives prepared during these synthesis have been subjected to screening assay. Alkylation and asymmetric reduction of 3, 4-dihydro-beta-carboline have been investigated. Pictet-Spengler reaction with Lewis acid and chiral Lewis acids was investigated. Total synthesis of some marine ceramides were also completed. 2. Survey of active principles towards central nervous system in fungi : 1) Monoamine oxidase inhibitory (MAOI) activity was surveyed in fungi and lichens in vitro. MAOI activity of norsolorinic acid from Emericella and TL-1 from Talaromyces fungi was exami … More ned in vivo on anti-reserpine action. 2) Anti-endotheline-1 (or -norepinephrine) potency of several Bornean folk medicines was investigated by using smooth muscle of rat blood vessel to screen hypotensive principles. 3) HS-A, -B, and -C were isolated from Basidiomyceste, Hebeloma spoliatum, as active principle relaxing mouse small intestine like papaverine. 4) A new metabolie NFA was isolated as an inflammatory principle from an Ascomycete, Neosartorya fischeri, besides the tremorgenic principles, fumitremorgin A and B. 3. Pharmacological evaluation of cerebral insufficiency improving activity : To screen and evaluate cerebral insufficiency improving activities of beta-carbolines, several pharmacological studies were conducted ; 1) cholecystokinin (CKK) related activity, 2), calcium blocking activities, 3) potentiation of cholinergic action and 4) GABA related activities. In isolated preparations, some of beta-carbolines showed a specific antagonism to CCK, and others exerted a vasodialative action which may be related to calcium blockade. Most of compounds showing CCK antagonism in vitro also blocked the CCK-induced locomotor depression. These may be most promising as lead compound with therapeutic application. Beside the above trials, some studies were done to elucidate central mechanism of drug action. Less