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Survey Investigation of Lead Compounds Towards Cerebral Insufficiency Improving Activity

铅化合物改善脑功能不全活性的调查研究

基本信息

批准号：
01870092
负责人：
HINO Tohru
金额：
$ 9.54万
依托单位：
Chiba University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Developmental Scientific Research
财政年份：
1989
资助国家：
日本
起止时间：
1989 至 1991
项目状态：
已结题

项目摘要

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

1. 合成-碳碱：以n -羟色胺和胱氨酸衍生物为原料，合成了多种海洋生物碱-碳碱生物碱。首次以1-甲氧基羰基甲基-羰基-碳碱和氮杂环癸烯为原料合成了海洋生物碱-碳胺C。同时合成了曼扎胺A的中心环体系吡咯异喹啉。在这些合成过程中制备的β -羰基衍生物的40多个化合物已经进行了筛选试验。研究了3,4 -二氢-羰基羰基的烷基化反应和不对称还原反应。研究了手性路易斯酸与路易斯酸的Pictet-Spengler反应。还完成了一些海洋神经酰胺的全合成。2. 真菌对中枢神经系统的作用机理研究：1)对真菌和地衣的单胺氧化酶抑制（MAOI）活性进行了研究。研究了采自Emericella的去盐酸和Talaromyces真菌的TL-1的mao活性。2)采用大鼠血管平滑肌筛选降压原理，考察几种婆罗洲民间药物的抗内皮素-1（或-去甲肾上腺素）效价。3)从担子菌中分离得到HS-A、-B和-C，其活性成分与罂粟碱类似，是放松小鼠小肠的活性成分。4)从一种子囊菌Neosartorya fischeri中分离出一种新的代谢因子NFA，作为促炎因子，除促炎因子fuitremorgin A和b外。脑功能不全改善活性的药理学评价：为了筛选和评价β -碳碱改善脑功能不全的活性，进行了多项药理研究；1)胆囊收缩素（CKK）相关活性，2)钙阻断活性，3)胆碱能作用增强，4)GABA相关活性。在分离制剂中，一些β -碳胺对CCK具有特异性拮抗作用，而另一些则具有血管舒张作用，这可能与钙阻断有关。大多数在体外显示CCK拮抗作用的化合物也能阻断CCK诱导的运动抑制。这些可能是最有希望作为先导化合物的治疗应用。除上述试验外，还进行了一些研究，以阐明药物作用的主要机制。少