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

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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