1996 Fiscal Year Annual Research Report

タイ薬用植物中のインドールアルカロイド類に関する創薬基礎科学研究

Research Project

Project/Area Number	06044035
Research Institution	Chiba University
Principal Investigator	坂井進一郎千葉大学, 名誉教授 (20009161)
Co-Investigator(Kenkyū-buntansha)	JOACHIM Stoc ドイツ, マインツ大学・薬学部, 教授 PANG Peter K カナダ, アルバータ大学・医学部, 教授 DHAVADEE Pon チュラロンコーン大学, 薬学部, 準教授 PAVICH Tongr チュラロンコーン大学, 薬学部, 準教授北島満里子千葉大学, 薬学部, 助手 (60195261) 堀江俊治千葉大学, 薬学部, 助手 (50209285) 高山廣光千葉大学, 薬学部, 助教授 (90171561) 矢野眞吾千葉大学, 薬学部, 助教授 (90009655) 渡辺裕司富山医科薬科大学, 和漢薬研, 教授 (10012642) 渡辺和夫千葉大学, 薬学部, 教授 (80019124) 相見則郎千葉大学, 薬学部, 教授 (30009170)
Keywords	タイ薬用植物 / Mitragyna speciosa / インドールアルカロイド / Mitragynine / 鎮痛活性 / セロトニン受容体 / オピオイド受容体 / Caチャンネル
Research Abstract	アカネ科植物ミトラガイナ・スペシオ-サ(Mitragyna speciosa)葉部は、タイ国内では“Kratom"、マレーシア国内では“Biak Biak"と呼ばれる伝承民間薬であり、麻薬様作用:中枢神経抑制効果(阿片様作用)と中枢神経興奮効果(コカイン様作用)及び止瀉作用が知られていた。本植物に含まれる有効成分に焦点を当てて、日本、タイ、ドイツ、カナダの研究者がそれぞれの専門領域の研究分野で協力することにより、化学と薬理の両面からの究明研究を行なった。化学面では、タイ産植物葉部の詳細な成分検索を行ない、主塩基Mitragynineと共に新化合物を含む数種の微量塩基を単離構造決定した。更に、主塩基Mitragynineの集約的ルートによる不斉全合成法を開拓することができた。また、Mitragynineの菌代謝産物として報告されたプソイドインドキシル体やMitragynineオキシインドールも化学変換により合成し、これらの立体化学を明らかにすると共に、薬理活性評価用献体として供した。更に、マレーシア産Mitrangyna speciosa葉部のアルカロイドについても化学的研究を行い、新規化合物の単離と共にピリドン型ミトラガイナアルカロイドの基本骨格合成を達成することができた。一方、薬理面での成果としては以下の点があげられる。主成分Mitragynineの中枢作用について検討を行い、Mitagynineに強力な鎮痛作用を見い出した。さらに末梢作用として、平滑筋伸縮抑制作用を見い出した。輸精管標本を用いた検討から、末梢作用の作用機序としてMitragynineが神経の節後線維に作用し、神経伝達物質の放出を抑制することが考えられた。神経由来細胞を用い、パッチクランプ、蛍光色素法などを駆使して解析した結果、Mitragynineの神経伝達物質遊離抑制作用には神経のT型およびL型Caチャネル遮断作用が関与していると推察した。また、モルモット回腸標本に用いた検討から、Mitragynineはオピオイド作用を有していることが判明した。その効力はMorphineの1/6であった。Mitragynineの微生物代謝物Pseudoindoxyl体にもオピオイド作用が認められ、その効力はMorphineの約20倍協力であった。そこで、これらの化合物についてオピオイド受容体結合実験を行い、両アルカロイドは特にμ受容体に親和性が高いことを見い出した。これらのMitragynineの末梢作用はその鎮痛作用機序に関連していると考えられる。 Mitragynineの構造に類似する釣藤鈎アルカロイドおおび母核のIndoloqunolitidine誘導体を用いて、オピオイド作用の構造活性相関的検討を行った。その結果、Mitragynineの9位メトキシル基が作用発現に必須であることが明らかとなった。また、そのメトキシル基と4位の窒素の位置関係が効力を左右していると推察した。また、Mitragynineの中枢作用に関する研究では以下の成果を得た。脳内5-HT2A受容体作動薬をマウスに投与すると、“首振り行動"が発現する。本行動に対するMitragynineの影響を検討した結果、Mitragynineは用量依存的な抑制効果を示した。Mitragynineの抑制作用はNoradrenaline枯渇薬及び5-HT枯渇薬の影響を受けず,α2受容体拮抗薬で解除されたことから、Mitragynineがシナプス後膜α2受容体刺激作用または5-HT2A受容体遮断作用を有することが示唆された。Mitragynineをマウスに腹腔内あるいは脳室内投与(i.c.v.)すると顕著な鎮痛作用が認められた。i.c.v.投与したMitragynineの鎮痛作用はオピオイド拮抗薬Naloxone(i.c.v.),α2受容体拮抗薬および5-HT受容体拮抗薬(i.c.v.,orくも膜下腔内投与)で抑制された。従って1)Mitragynine自身が脳内で作用して鎮痛作用を発現しうること,および2)この鎮痛作用に上位オピオイド受容体及び下降性モノアミン神経系が関与することが推察される。この様に、ミトラガイナアルカロイドに種々の特異的かつ有効な薬理活性が見された。これらアルカロイドは今後、医薬品の開発、薬理作用機序の観点から興味深い素材と考えられる。上記研究と平行して、タイ産Uncaria,Nauclea,Hunteria、及びVernonia属植物の化学的検索及び薬理学的評価も実施した。

Research Products

(43 results)

All Other

All Publications (43 results)

[Publications] H.Takayama: "A New Class of Two Dimeric Indole Alkaloids,Coryzeylamine and Deformylcoryzeylamine from the Leaves of Hunteria zeylanica in Thailand." Chem.Pharm.Bull.42. 1957-1959 (1994)
[Publications] S.Sakai: "Biomimetic Chemical Transformation from Simple Indole Alkaloids to Gelsemium Alkaloids." Pure&Appl.Chem.66. 2139-2142 (1994)
[Publications] W.Reanmongkol: "Antinocicetive and Antipyretic Effects of Alkaloids Extracted from the Stem Bark of Hunteria zeylanica." Biol.Pharm.Bull.17. 1345-1350 (1994)
[Publications] S.Subhadhirasakul: "New Corymine-Related Indole Alkaloids from Hunteria zeylanica in Thailand." Chem.Pharm.Bull.42. 2645-2646 (1994)
[Publications] H.Takayama: "A Biomimetic Synthesis of a New Skeletal Gelsemium Alkaloid,11-Methoxy-19(R)-bydroxygelselegine." Tetrahedron. 50. 11813-11820 (1994)
[Publications] H.Takayama: "On the Indole Alkaloids,Nauclefidine ; Structure Revision,Synthesis,and A Biomimetic Transformation from the Vincoside Lactam." Tetrahedron Lett.35. 8813-8816 (1994)
[Publications] S.Subhadhirasakul: "Hunterioside,First Biose Bound Monoterpenoid Indole Alkaloid from Hunteriazeylanica." Chem.Pharm.Bull.42. 991-993 (1994)
[Publications] S.Subhadhirasakul: "Novel Indole Alkaloids from the leaves of Rauwolfia sumatrana Jack.in Thailand." Chem.Pharm.Bull.42. 1427-1431 (1994)
[Publications] M.Kitajima: "Synthesis of a Novel Gelsedine-Type Gelsemium Alkaloid,Gelsemicine." J.Chem.Soc.,Perkin Trnans.1. 1573-1578 (1994)
[Publications] H.Takayama: "Fist Synthesis of the Novel Gelsemium Alkaloids,Gelselegine,Gelsenicine,and Gelsedine Using a Biomimetic Approach." J.Org.Chem.59. 4381-4385 (1994)
[Publications] H.Takayama: "A Biomimetic Synthesis of a Novel Seco Indole Alkaloid,11-Methoxygelsemamide." Tetrahedron. 50. 8363-8370 (1994)
[Publications] H.Takayama: "Two New Iridoids from the Leaves of Gelsemium elegans Benth.in Thailand." Natural Product Lett.5. 15-20 (1994)
[Publications] D.Pouglux: "A New Indole Alkalaid,7α-Hydroxy-7II-mitragynine,from Mitragyna speciosa in Thailand." Planta Medica. 60. 580-581 (1994)
[Publications] N.Keawpradub: "Indole Alkaloids from Alstonia glaucescens." Phytochemistry. 37. 1745-1749 (1994)
[Publications] W.Reanmongkol: "Effects of Alkaloids Extracted from the Stem Bark of Hunteria zeylanica on acute Inflammation in Experimental Animals." Biol.Pharm.Bull.18. 33-36 (1995)
[Publications] W.Reanmongkol: "Inhibitory Effect of Alkaloids Extracted from the Stem Bark of Hunteria zeylanica on 5-Lipoxygenase Activity in vitro." Biol.Pharm.Bull.18. 910-912 (1995)
[Publications] S.Sakai: "Chemistry of Indole Alkaloids." Yakugaku Zasshi. 115. 351-369 (1995)
[Publications] S.Subhadhirasakul: "Two Novel Sarpagine-type Indole Alkaloids from the Leaves of Hunteria zeylanica in Thailand." Heterocycles. 41. 2049-2056 (1995)
[Publications] H.Takayama: "Synthesis and Conformational Analysis of a New Indole Alkaloid,2,7-Dihydroxyapogeissoschizine." Natural Prod.Lett.7. 81-84 (1995)
[Publications] H.Falkenhagen: "Substrate Specificity of Vinorine Hydroxylase,A Novel Membrane-Bound Key Enzyme of Rauwolfia Indole Alkaloid Biosynthesis" Heterocycles. 41. 2683-2690 (1995)
[Publications] H.Takayama: "The Frst Total Synthesis of (-)-Mitragynine,An Analgesic Indole Alkaloid in Mitragyna speciosa." Tetrahedron Lett.36. 9337-9340 (1995)
[Publications] W-C.Lin,: "Effect of intracerebroventricular and intrahypothalamic administrations of picrotoxin on basal and stimulated gastric acid secretion." Res.Commun.Mol.Puthol.Pharmacol. 89. 143-156 (1995)
[Publications] S.Yano: "Pharmacological Features of Nonadrenergic Noncholinergic (NANC) relaxation Induced by Electrical Vagal Stimulation in Isolated Mouse Stomach." Jpn.J.Pharmacol.69. 9-15 (1995)
[Publications] S.Horie: "Intracellular alkalinazation by NH4Cl increases cytosolic Ca level and tension in the rat aortic smooth muscle." Life Sciences. 56. 1835-1843 (1995)
[Publications] Q.Y.Liu: "Tetrandrine,a Ca Antagonist : Effects and Mechanisms of Action in Vascular Smooth Muscle Cells." J.Pharmacol.Exp.Ther.273. 32-39 (1995)
[Publications] K.W.Chiu: "Cardiovascular Active Substances from the Straw Mushroom.Volvariella Volvarea." Phytotherapy Reserch. 9. 93-99 (1995)
[Publications] M.Barbagallo: "Glucose-induced Alterations of Cytosolic Free Calcium in Culture Rat Tail Artery Vascular Smooth Muscle Cells." J.Clin.Invest.95. 763-767 (1995)
[Publications] L.W.Kline: "The Effect of Body Weight on the Calcitonin Gene-related Peptide-induced Relaxation of Guinea-pig Gallbladder Strips." Regulatory Peptides. 59. 97-101 (1995)
[Publications] H.Takayama: "Stereochemical Assignment of Pseudoindoxyl Alkaloids." Heterocycles. 42. 87-92 (1996)
[Publications] S.Thongpraditchote: "Neuropharmacological Actions of Plucher indica Less Root Extract in Socially Isolated Mice." Bio.Pharm.Bull.19. 379-383 (1996)
[Publications] N.Aimi: "Isolation of Alkaloids from Cultured Hybrid Cells of Rauwolfia serpentina x Rhazya stricta." Chem.Pharm.Bull.44. 1637-1639 (1996)
[Publications] K.Matsumoto: "Antinociceptive Action of Mitragynine in Mice : Evidence for the Involvement of Supraspinal Opioid Receptors." Life Sciences. 59. 1149-1155 (1996)
[Publications] S.A.Achmad: "A New Prenylated Flavone from Artocarpus champeden." J.Nat.Prod.59. 878-879 (1996)
[Publications] H.Takayama: "Biomimetic Synthesis of Nauclea Indole Alkaloids,Naucleidinal,and 3-epi-Naucleidinal." Chem.Pharm.Bull.44. 2192-2194 (1996)
[Publications] M.Kitajima: "Structure and Synthesis of a New Chiral β-Carboline Found in Cultured Cell Clumps of Rauwolfia serpentina x Rhazya stricta." Chem.Pharm.Bull.44. 2195-2197 (1996)
[Publications] K.Matsumoto: "Central Antinociceptive Effects of Mitragynine in Mice : Contribution of Descending Noradrenergic and Serotonergic Systems." Eur.J.Pharmacol.317. 75-81 (1996)
[Publications] P.Leewanich: "Behavioral studies on alkaloids extracted from the leaves of Hunteria zeylanica." Biol.Pharm.Bull.19. 394-399 (1996)
[Publications] S.Horie: "Neurogenic Stimulation of Gastric Acid Secretion by the Na,K-ATPase Inhibitor Ouabain in Mouse Isolated Stomach." Gen.Pharmacol.27. 905-909 (1996)
[Publications] K.Watanabe: "Inhibitory Effect of Mitragynine,an Alkaloid with Analgesic Effect from Tai Medicinal Plant Mitragyna speciosa,on Electrically Stimulated Contraction of Isolated Guinea-Pig Ileum through Opioid Receptor." Life Sciences. 60. 933-942 (1997)
[Publications] K.Matsumoto: "Suppressive effect of mitragynine on the 5-methoxy-N,N-dimethyltryptamine-induced head twitch response in mice." Pharmacol.Biochem.Behav.(in press). (1997)
[Publications] S.Thongpraditchote: "Effect of mitragynine on cyclic AMP production induced by forskolin in NG108-15 cells." Biol.Pharm.Bull.20(in press). (1997)
[Publications] H.Takayama: "Studies in Natural Product Chemistry Vol.15 Recent Advances in the Chemistry of Gelsemium Alkaloids." Elsevier, 53 (1995)
[Publications] P.Obitz: "Alkaloids : Chemical and Biological Perspectives Alkaloids from Cell Cultures of Aspidosperma Quebracho-Blanco." Elsevier, 11 (1995)

1996 Fiscal Year Annual Research Report

タイ薬用植物中のインドールアルカロイド類に関する創薬基礎科学研究

Principal Investigator

坂井 進一郎 千葉大学, 名誉教授 (20009161)

Research Products

[Publications] H.Takayama: "A New Class of Two Dimeric Indole Alkaloids,Coryzeylamine and Deformylcoryzeylamine from the Leaves of Hunteria zeylanica in Thailand." Chem.Pharm.Bull.42. 1957-1959 (1994)

[Publications] S.Sakai: "Biomimetic Chemical Transformation from Simple Indole Alkaloids to Gelsemium Alkaloids." Pure&Appl.Chem.66. 2139-2142 (1994)

[Publications] W.Reanmongkol: "Antinocicetive and Antipyretic Effects of Alkaloids Extracted from the Stem Bark of Hunteria zeylanica." Biol.Pharm.Bull.17. 1345-1350 (1994)

[Publications] S.Subhadhirasakul: "New Corymine-Related Indole Alkaloids from Hunteria zeylanica in Thailand." Chem.Pharm.Bull.42. 2645-2646 (1994)

[Publications] H.Takayama: "A Biomimetic Synthesis of a New Skeletal Gelsemium Alkaloid,11-Methoxy-19(R)-bydroxygelselegine." Tetrahedron. 50. 11813-11820 (1994)

[Publications] H.Takayama: "On the Indole Alkaloids,Nauclefidine ; Structure Revision,Synthesis,and A Biomimetic Transformation from the Vincoside Lactam." Tetrahedron Lett.35. 8813-8816 (1994)

[Publications] S.Subhadhirasakul: "Hunterioside,First Biose Bound Monoterpenoid Indole Alkaloid from Hunteriazeylanica." Chem.Pharm.Bull.42. 991-993 (1994)

[Publications] S.Subhadhirasakul: "Novel Indole Alkaloids from the leaves of Rauwolfia sumatrana Jack.in Thailand." Chem.Pharm.Bull.42. 1427-1431 (1994)

[Publications] M.Kitajima: "Synthesis of a Novel Gelsedine-Type Gelsemium Alkaloid,Gelsemicine." J.Chem.Soc.,Perkin Trnans.1. 1573-1578 (1994)

[Publications] H.Takayama: "Fist Synthesis of the Novel Gelsemium Alkaloids,Gelselegine,Gelsenicine,and Gelsedine Using a Biomimetic Approach." J.Org.Chem.59. 4381-4385 (1994)

[Publications] H.Takayama: "A Biomimetic Synthesis of a Novel Seco Indole Alkaloid,11-Methoxygelsemamide." Tetrahedron. 50. 8363-8370 (1994)

[Publications] H.Takayama: "Two New Iridoids from the Leaves of Gelsemium elegans Benth.in Thailand." Natural Product Lett.5. 15-20 (1994)

[Publications] D.Pouglux: "A New Indole Alkalaid,7α-Hydroxy-7II-mitragynine,from Mitragyna speciosa in Thailand." Planta Medica. 60. 580-581 (1994)

[Publications] N.Keawpradub: "Indole Alkaloids from Alstonia glaucescens." Phytochemistry. 37. 1745-1749 (1994)

[Publications] W.Reanmongkol: "Effects of Alkaloids Extracted from the Stem Bark of Hunteria zeylanica on acute Inflammation in Experimental Animals." Biol.Pharm.Bull.18. 33-36 (1995)

[Publications] W.Reanmongkol: "Inhibitory Effect of Alkaloids Extracted from the Stem Bark of Hunteria zeylanica on 5-Lipoxygenase Activity in vitro." Biol.Pharm.Bull.18. 910-912 (1995)

[Publications] S.Sakai: "Chemistry of Indole Alkaloids." Yakugaku Zasshi. 115. 351-369 (1995)

[Publications] S.Subhadhirasakul: "Two Novel Sarpagine-type Indole Alkaloids from the Leaves of Hunteria zeylanica in Thailand." Heterocycles. 41. 2049-2056 (1995)

[Publications] H.Takayama: "Synthesis and Conformational Analysis of a New Indole Alkaloid,2,7-Dihydroxyapogeissoschizine." Natural Prod.Lett.7. 81-84 (1995)

[Publications] H.Falkenhagen: "Substrate Specificity of Vinorine Hydroxylase,A Novel Membrane-Bound Key Enzyme of Rauwolfia Indole Alkaloid Biosynthesis" Heterocycles. 41. 2683-2690 (1995)

[Publications] H.Takayama: "The Frst Total Synthesis of (-)-Mitragynine,An Analgesic Indole Alkaloid in Mitragyna speciosa." Tetrahedron Lett.36. 9337-9340 (1995)

[Publications] W-C.Lin,: "Effect of intracerebroventricular and intrahypothalamic administrations of picrotoxin on basal and stimulated gastric acid secretion." Res.Commun.Mol.Puthol.Pharmacol. 89. 143-156 (1995)

[Publications] S.Yano: "Pharmacological Features of Nonadrenergic Noncholinergic (NANC) relaxation Induced by Electrical Vagal Stimulation in Isolated Mouse Stomach." Jpn.J.Pharmacol.69. 9-15 (1995)

[Publications] S.Horie: "Intracellular alkalinazation by NH4Cl increases cytosolic Ca level and tension in the rat aortic smooth muscle." Life Sciences. 56. 1835-1843 (1995)

[Publications] Q.Y.Liu: "Tetrandrine,a Ca Antagonist : Effects and Mechanisms of Action in Vascular Smooth Muscle Cells." J.Pharmacol.Exp.Ther.273. 32-39 (1995)

[Publications] K.W.Chiu: "Cardiovascular Active Substances from the Straw Mushroom.Volvariella Volvarea." Phytotherapy Reserch. 9. 93-99 (1995)

[Publications] M.Barbagallo: "Glucose-induced Alterations of Cytosolic Free Calcium in Culture Rat Tail Artery Vascular Smooth Muscle Cells." J.Clin.Invest.95. 763-767 (1995)

[Publications] L.W.Kline: "The Effect of Body Weight on the Calcitonin Gene-related Peptide-induced Relaxation of Guinea-pig Gallbladder Strips." Regulatory Peptides. 59. 97-101 (1995)

[Publications] H.Takayama: "Stereochemical Assignment of Pseudoindoxyl Alkaloids." Heterocycles. 42. 87-92 (1996)

[Publications] S.Thongpraditchote: "Neuropharmacological Actions of Plucher indica Less Root Extract in Socially Isolated Mice." Bio.Pharm.Bull.19. 379-383 (1996)

[Publications] N.Aimi: "Isolation of Alkaloids from Cultured Hybrid Cells of Rauwolfia serpentina x Rhazya stricta." Chem.Pharm.Bull.44. 1637-1639 (1996)

[Publications] K.Matsumoto: "Antinociceptive Action of Mitragynine in Mice : Evidence for the Involvement of Supraspinal Opioid Receptors." Life Sciences. 59. 1149-1155 (1996)

[Publications] S.A.Achmad: "A New Prenylated Flavone from Artocarpus champeden." J.Nat.Prod.59. 878-879 (1996)

[Publications] H.Takayama: "Biomimetic Synthesis of Nauclea Indole Alkaloids,Naucleidinal,and 3-epi-Naucleidinal." Chem.Pharm.Bull.44. 2192-2194 (1996)

[Publications] M.Kitajima: "Structure and Synthesis of a New Chiral β-Carboline Found in Cultured Cell Clumps of Rauwolfia serpentina x Rhazya stricta." Chem.Pharm.Bull.44. 2195-2197 (1996)

[Publications] K.Matsumoto: "Central Antinociceptive Effects of Mitragynine in Mice : Contribution of Descending Noradrenergic and Serotonergic Systems." Eur.J.Pharmacol.317. 75-81 (1996)

[Publications] P.Leewanich: "Behavioral studies on alkaloids extracted from the leaves of Hunteria zeylanica." Biol.Pharm.Bull.19. 394-399 (1996)

[Publications] S.Horie: "Neurogenic Stimulation of Gastric Acid Secretion by the Na,K-ATPase Inhibitor Ouabain in Mouse Isolated Stomach." Gen.Pharmacol.27. 905-909 (1996)

[Publications] K.Watanabe: "Inhibitory Effect of Mitragynine,an Alkaloid with Analgesic Effect from Tai Medicinal Plant Mitragyna speciosa,on Electrically Stimulated Contraction of Isolated Guinea-Pig Ileum through Opioid Receptor." Life Sciences. 60. 933-942 (1997)

[Publications] K.Matsumoto: "Suppressive effect of mitragynine on the 5-methoxy-N,N-dimethyltryptamine-induced head twitch response in mice." Pharmacol.Biochem.Behav.(in press). (1997)

[Publications] S.Thongpraditchote: "Effect of mitragynine on cyclic AMP production induced by forskolin in NG108-15 cells." Biol.Pharm.Bull.20(in press). (1997)

[Publications] H.Takayama: "Studies in Natural Product Chemistry Vol.15 Recent Advances in the Chemistry of Gelsemium Alkaloids." Elsevier, 53 (1995)

[Publications] P.Obitz: "Alkaloids : Chemical and Biological Perspectives Alkaloids from Cell Cultures of Aspidosperma Quebracho-Blanco." Elsevier, 11 (1995)

坂井進一郎千葉大学, 名誉教授 (20009161)