1991 Fiscal Year Annual Research Report

脳機能改善薬を志向したリ-ド化合物の探索研究

Research Project

Project/Area Number	01870092
Research Institution	Chiba University
Principal Investigator	日野亨千葉大学, 薬学部, 教授 (10009160)
Co-Investigator(Kenkyū-buntansha)	渡辺和夫千葉大学, 薬学部, 教授 (80019124) 山崎幹夫千葉大学, 薬学部, 教授 (70089598) 中川昌子千葉大学, 薬学部, 助教授 (40009171)
Keywords	脳機能改善薬 / β-カルボリン / スフィンゴ脂質 / ユ-ディストミン / 向中枢神経作用物質 / モノアミン酸化酵素 / 子嚢菌 / 胃液分泌中枢性調節
Research Abstract	1.β-カルボリン類の合成:前年度渡辺グル-プで薬理作用を検討し、その考察より考案されたβ-カルボリン化合物数種を合成し薬理スクリ-ニングに供した。光学活性1-置換-テトラヒドロ-β-カルボリンをその3、4-ジヒドロ体の不斉還元により合成する方法を検討し、40%程度の光学収率で得られることを明かにした。この不斉還元を、より一般的なC=Nの還元に応用した。また、マンザミン類、ユ-ディストミン関連化合物の合成を続行し、数種のアナロ-グの合成に成功した。さらにPictet-Spengler反応を光学活性Lewis酸で行う反応条件を検討し、新しい知見を得た。2.スフィンゴ脂質の合成:海洋産セラミドであるシンビオラミドの合成法を確立し、その絶対構造を明かにした。3.向中枢神経作用成分の探索:子嚢菌4種、地衣類34種についてマウス肝モノアミン酸化酵素を用いて阻害活性を検討し、子嚢菌3種、地衣類1種に高活性が認められた。子嚢菌Talaromyces luteusより阻害活性成分のTL-1,-2と共に新関連化合物のTL-3,-4を単離し構造を解明した。さらにTL-1について、マウスを用いるin vivoの実験で一部は肝および脳に移行していることを明かにした。4.β-カルボリン類緑体の薬理作用の解析:合成したβ-カルボリン43種を含む化合物の薬効スクリ-ニングからリ-ド化合物として興味ある薬物を数種選定し、さらに薬理学的プロフィルを解析した。その結果1)胆嚢平滑筋においてCCK-8に特異的に比較的つよく拮抗を示す化合物はいずれもテトラヒドロ-β-カルボリン系であった。2)CCK-8の自発運動抑制に対してある種の化合物は拮抗作用を示し、中枢に作用することが判明した。この作用は脳機能改善薬を開発する上のリ-ド化合物の資格を持つと考えられた。3)胆嚢平滑筋において収縮作用を示すβ-カルボリン誘導体を見出したが、胃酸分泌作用に対する影響はなかった。

Research Products
(15 results)

All Other

All Publications (15 results)

[Publications] 劉進軍: "The Pictet-Spengler reaction of Nb-hydroxytryptamines and cysteinals.II.Temperature effects,stereochemistry and mechanism." Chem.Pharm.Bull.39. 1672-1676 (1991)
[Publications] 鳥澤保廣: "A total synthesis of manzamine C and its geometrical isomer." Tetrahedron. 38. 8067-8078 (1991)
[Publications] 日野亨: "スフィンゴ糖脂質の合成。" フアルマシア. 27. 1164-1189 (1991)
[Publications] 川手智彦: "A new evidence for the presence of a spiro indolenium species in the Pictet-Spengler reaction." Heterocycles. 1992.
[Publications] 川手智彦: "Asymmetric reduction of imines with chiral dialkoxyboranes." Tetrahedron Asymmetry. 1992.
[Publications] 吉田淳: "Total synthesis of symbioramide,a novel Ca^<2+>-ATPase activator from Symbiodinium sp." J.Chem.Soc.Perkin Trans.I. 1992.
[Publications] 奥山恵美: "Monoamine Oxidase Inhibitors from a Lichen,Solorina crocea(L.)Ach.." Shoyakugaku Zasshi. 45. 159-162 (1991)
[Publications] 藤本治宏: "New Toxic Metabolites.from aMushroom,Hebeloma Vinosophyllum.III.Isolation and Structures of Three New Glycosides,Hebevinosides XII,XIII and XIV,and Productivity of.the Hebevinosides at Three Growth Stages of the Mushroom." Chem.Pharm.Bull.39. 1958-1961 (1991)
[Publications] 藤本治宏: "Isolation,Identification and Pharmacological Studies on Three Toxic Metabolites from a Mushroom,Hebeloma spoliatum." Chem.Pharm.Bull.40. (1992)
[Publications] 奥山恵美: "Analgesic Principles from a Bornean Medicinal Plant,Tabernamontana Pauciflora Blume." Chem.Pharm.Bull.
[Publications] 内田勝幸: "The role of capsaicin-sensitive afferent nerves in protective effect of capsaicin against absolute ethanol-induced gastric lesions in rats." Japan.J.Pharmacol.55. 279-282 (1991)
[Publications] 内田勝幸: "A reliable method for the production of antral gastric ulcer by a combination of 2-deoxy-D-glucose,aspirin and ammonia in rats." Japan.J.Pharmacol.55. 475-481 (1991)
[Publications] 内田勝幸: "Aggravation by the capsaicin-treatment of gastric antral ulcer induced by the combination of 2-deoxy-D-glucose,aspirin and ammonia in rats." Japan.J.Pharmacol.57. 377-385 (1991)
[Publications] 矢野真吾: "Ca^<2+> channel blocking effects of hirsutine,an indole alkaloid from uncaria Genus,in the isolated rat aorta." Planta Med.57. 403-405 (1991)
[Publications] 堀江俊治: "Effects of hirusutine,an antihypertensive indole alkaloid from uncaria rhynchophylla,on intracellular calcium in rat thoracic aorta." Life Sciences. 50. 491-498 (1992)

1991 Fiscal Year Annual Research Report

脳機能改善薬を志向したリ-ド化合物の探索研究

Principal Investigator

日野 亨 千葉大学, 薬学部, 教授 (10009160)

Research Products

[Publications] 劉 進軍: "The Pictet-Spengler reaction of Nb-hydroxytryptamines and cysteinals.II.Temperature effects,stereochemistry and mechanism." Chem.Pharm.Bull.39. 1672-1676 (1991)

[Publications] 鳥澤 保廣: "A total synthesis of manzamine C and its geometrical isomer." Tetrahedron. 38. 8067-8078 (1991)

[Publications] 日野 亨: "スフィンゴ糖脂質の合成。" フアルマシア. 27. 1164-1189 (1991)

[Publications] 川手 智彦: "A new evidence for the presence of a spiro indolenium species in the Pictet-Spengler reaction." Heterocycles. 1992.

[Publications] 川手 智彦: "Asymmetric reduction of imines with chiral dialkoxyboranes." Tetrahedron Asymmetry. 1992.

[Publications] 吉田 淳: "Total synthesis of symbioramide,a novel Ca^<2+>-ATPase activator from Symbiodinium sp." J.Chem.Soc.Perkin Trans.I. 1992.

[Publications] 奥山 恵美: "Monoamine Oxidase Inhibitors from a Lichen,Solorina crocea(L.)Ach.." Shoyakugaku Zasshi. 45. 159-162 (1991)

[Publications] 藤本 治宏: "New Toxic Metabolites.from aMushroom,Hebeloma Vinosophyllum.III.Isolation and Structures of Three New Glycosides,Hebevinosides XII,XIII and XIV,and Productivity of.the Hebevinosides at Three Growth Stages of the Mushroom." Chem.Pharm.Bull.39. 1958-1961 (1991)

[Publications] 藤本 治宏: "Isolation,Identification and Pharmacological Studies on Three Toxic Metabolites from a Mushroom,Hebeloma spoliatum." Chem.Pharm.Bull.40. (1992)

[Publications] 奥山 恵美: "Analgesic Principles from a Bornean Medicinal Plant,Tabernamontana Pauciflora Blume." Chem.Pharm.Bull.

[Publications] 内田 勝幸: "The role of capsaicin-sensitive afferent nerves in protective effect of capsaicin against absolute ethanol-induced gastric lesions in rats." Japan.J.Pharmacol.55. 279-282 (1991)

[Publications] 内田 勝幸: "A reliable method for the production of antral gastric ulcer by a combination of 2-deoxy-D-glucose,aspirin and ammonia in rats." Japan.J.Pharmacol.55. 475-481 (1991)

[Publications] 内田 勝幸: "Aggravation by the capsaicin-treatment of gastric antral ulcer induced by the combination of 2-deoxy-D-glucose,aspirin and ammonia in rats." Japan.J.Pharmacol.57. 377-385 (1991)

[Publications] 矢野 真吾: "Ca^<2+> channel blocking effects of hirsutine,an indole alkaloid from uncaria Genus,in the isolated rat aorta." Planta Med.57. 403-405 (1991)

[Publications] 堀江 俊治: "Effects of hirusutine,an antihypertensive indole alkaloid from uncaria rhynchophylla,on intracellular calcium in rat thoracic aorta." Life Sciences. 50. 491-498 (1992)

日野亨千葉大学, 薬学部, 教授 (10009160)

[Publications] 劉進軍: "The Pictet-Spengler reaction of Nb-hydroxytryptamines and cysteinals.II.Temperature effects,stereochemistry and mechanism." Chem.Pharm.Bull.39. 1672-1676 (1991)

[Publications] 鳥澤保廣: "A total synthesis of manzamine C and its geometrical isomer." Tetrahedron. 38. 8067-8078 (1991)

[Publications] 日野亨: "スフィンゴ糖脂質の合成。" フアルマシア. 27. 1164-1189 (1991)

[Publications] 川手智彦: "A new evidence for the presence of a spiro indolenium species in the Pictet-Spengler reaction." Heterocycles. 1992.

[Publications] 川手智彦: "Asymmetric reduction of imines with chiral dialkoxyboranes." Tetrahedron Asymmetry. 1992.

[Publications] 吉田淳: "Total synthesis of symbioramide,a novel Ca^<2+>-ATPase activator from Symbiodinium sp." J.Chem.Soc.Perkin Trans.I. 1992.

[Publications] 奥山恵美: "Monoamine Oxidase Inhibitors from a Lichen,Solorina crocea(L.)Ach.." Shoyakugaku Zasshi. 45. 159-162 (1991)

[Publications] 藤本治宏: "New Toxic Metabolites.from aMushroom,Hebeloma Vinosophyllum.III.Isolation and Structures of Three New Glycosides,Hebevinosides XII,XIII and XIV,and Productivity of.the Hebevinosides at Three Growth Stages of the Mushroom." Chem.Pharm.Bull.39. 1958-1961 (1991)

[Publications] 藤本治宏: "Isolation,Identification and Pharmacological Studies on Three Toxic Metabolites from a Mushroom,Hebeloma spoliatum." Chem.Pharm.Bull.40. (1992)

[Publications] 奥山恵美: "Analgesic Principles from a Bornean Medicinal Plant,Tabernamontana Pauciflora Blume." Chem.Pharm.Bull.

[Publications] 内田勝幸: "The role of capsaicin-sensitive afferent nerves in protective effect of capsaicin against absolute ethanol-induced gastric lesions in rats." Japan.J.Pharmacol.55. 279-282 (1991)

[Publications] 内田勝幸: "A reliable method for the production of antral gastric ulcer by a combination of 2-deoxy-D-glucose,aspirin and ammonia in rats." Japan.J.Pharmacol.55. 475-481 (1991)

[Publications] 内田勝幸: "Aggravation by the capsaicin-treatment of gastric antral ulcer induced by the combination of 2-deoxy-D-glucose,aspirin and ammonia in rats." Japan.J.Pharmacol.57. 377-385 (1991)

[Publications] 矢野真吾: "Ca^<2+> channel blocking effects of hirsutine,an indole alkaloid from uncaria Genus,in the isolated rat aorta." Planta Med.57. 403-405 (1991)

[Publications] 堀江俊治: "Effects of hirusutine,an antihypertensive indole alkaloid from uncaria rhynchophylla,on intracellular calcium in rat thoracic aorta." Life Sciences. 50. 491-498 (1992)