Studies on the beta-Carboline Derivatives as Lead Compounds of Therapeutics for Brain-Gut and Central Nervous Diseases

我们项目的主题一直集中在β -碳碱改善脑部疾病的药物，我们评估了β -碳碱对中枢神经系统的影响。研究结果主要有以下三点：(1)开发了两种手性-羰基羰基衍生物的合成方法，用于生物活性测试。以1-苯乙基或1-（1-萘基）乙基为手性助剂的醛类与色胺类的Pictet-Spengler （P-S）反应产生具有高非对映选择性的1-取代四氢-碳胺类化合物。这些助剂通过简单的氢解去除。我们还发现了试剂控制的对映选择性P-S反应的第一个例子。以nb -羟色胺为原料，在二异戊二苯基氯硼烷或Br_nsted酸辅助Lewis酸存在下制备的硝基酮与醛的P-S反应可获得光学活性高达91%的2-羟基四氢- β -碳胺。对天然来源的真菌和生药中的嗜神经成分进行了调查，发现许多嗜神经成分包括致震颤的四氢- - -碳碱、单胺氧化酶抑制成分、子囊菌的免疫调节成分，以及对醋酸致小鼠扭体有抑制作用的- - -碳碱、镇痛成分等。从南美、中国、日本和东南亚的几种传统药材中分离出抗焦虑成分。研究了它们的分子结构和构效关系。(3)阐明了泰国药用植物米特拉吉那（Mitragyna speciosa）的药理活性和β -碳碱类活性原理。我们利用各种药理学方法阐明了米特拉金的活性成分的阿片性质。此外，还发现钩毛藤中与米特拉金碱化学结构相似的成分不表现出阿片活性，但与阿片受体结合强烈。我们设计了新颖实用的胃酸分泌定量测量方法，通过这些方法阐明了中枢神经通过各种神经递质调控胃酸分泌的机制。少

The theme of our project has been focused on beta-carboIines for improving drugs for brain disorder, and we evaluated the effects of beta-carbolines on central nervous system. The results are summarized in the following three points :(1) We have developed two methods for the synthesis of chiral beta-carboline derivatives for the test of biological activities. Pictet-Spengler (P-S) reaction of aldehydes and tryptamines, which have chiral 1- phenylethyl or 1-(1-naphtyl)ethyl group as chiral auxiliaries, afforded 1-substituted tetrahydro-beta- carbolines with high diastereoselectivities. These auxiliaries were removed by simple hydrogenolysis. We have also found the first example of a reagent-controlled enantioselective P-S reaction. P-S reaction of nitrones, which were prepared from Nb-hydroxytryptamine with aldehydes, in the presence of diisopinocampheylchloroborane or Br_nsted acid-assisted Lewis acids afforded optically active 2- hydroxytetrahydro-beta-carbolines in up to 91 % ee.(2) … More On a survey of neurotropic components from fungi and crude drugs as natural sources, many neurotropic compounds including tremorgenic tetrahydro-beta-carbolines, monoamine oxidase inhibitory components, and immunomodulatory constituents from Ascomycetes, and those including beta-carbolines which possessed suppressive effect on writhing induced by acetic acid in mice, analgesic components, and anti-anxiolytic constituents from several traditional crude drugs used in South America, China, Japan, and Southeast Asia were isolated. Their molecular structures and structure-activity relationship were elucidated.(3) We have clarified the pharmacological activities and beta-carboline type active principles of Thai medicinal plant, Mitragyna speciosa. We have elucidated the opioid character of the active component mitragynine by using various pharmacological methods. Furthermore, it was also found that the constituents in Uncaria hook, hirsutine that has similar chemical structure to mitragynine did not show opioid activity, but strongly bound to opioid receptors. We have devised original and useful methods for the quantitative measurement of gastric acid secretion, by using these methods we have clarified central nervous control mechanisms of gastric acid secretion via various neurotransmitters. Less