1992 Fiscal Year Annual Research Report

神経伝達機構に作用する高度活性物質の開発

Research Project

Project/Area Number	04554021
Research Institution	Hokkaido University
Principal Investigator	白濱晴久北海道大学, 理学部, 教授 (00000802)
Co-Investigator(Kenkyū-buntansha)	大船泰史 (財)サントリー生物有機科学研究所, 主任研究員 (20142078) 篠崎温彦 (財)東京都臨床医学総合研究所, 薬理研究室長 (20109945)
Keywords	アクロメリン酸B / グルタメート受容体 / 光照射下のジールズアルダー反応 / ピロリジン環の効率的形成 / カルボキシシクロプロピルグリシン / 立体配座解析
Research Abstract	1.アクロメリン酸B(Acro B)の効率的合成。標題化合物はグルタメートリセプターに強く作用し、強い神経の興奮を惹き起す。そのため薬理学研究の重要な試薬になると予想される。しかし、現在までのところ、いくつかの合成法が発表されたとは云え、これを試薬として薬理学界に提供できる程の量を合成するのに適した方法は、発表されていない。そこでわれわれは、先に発表した光照射による芳香族アルデヒドのエノル化によって生じたジエンに対するDielsーAlder反応を利用してAcro Bを効率よく合成する方法を検討し、通算21%の収率で得られる方法を開発した。即ち2-シアノピリジルエタノールトリフレートとビニルオキサゾリドンを縮合し、数段階を経て合成したピリジンアルデヒド1を光照射下に環化させ、立体選択的にピロリジン環を形成した。β-ケト酸部分をアルカリで切断したのち数段階を経て、Acro Bとした。 2.Lー2ー(カルボキシシクロプロピル)グリシン(CCG)類の配座解析。先にわれわれが開発したLー2-(カルボキシシクロプロピル)グリシン(CCG)類はグルタミン酸受容体の選択的かつ強力なアゴニストであり、神経科学研究の重要なツールとして用いられている。今回、CCG類をグルタミン酸受容体の立体配座要請の解明のためのプローブと考え、数種のCCG類の3'ー位置換体を合成しそれらの活性の検討とともにCCG類とあわせ分光学的手法により立体配座解析をおこなった。その結果、受容体の活性化におけるグルタミン酸の立体配座に関して重要な見知を得た。また、新しいアゴニストも開発できた。

Research Products

(23 results)

All Other

All Publications (23 results)

[Publications] M.Tanaka: "Neurotoxic Oligoisoprenoids of Hallucinogenic Mushroom,Gymnopilus spectabilis" Phytochemistry. 32. (1993)
[Publications] K.Yamano: "New Amino Acids from Clitocybe acromelalga.Possible Intermediates in the Biogenesis of Mushroom Toxins,Acromelic Acids" Tetrahedron. 49. (1993)
[Publications] K.Yamano: "Isolation of L-N-[2-(3-Pyridyl)ethyl]-glutamic Acid from the Poisonous Mushroom Clitocybe acromelalga.A Possible Intermediate in the Biogenes is of Acromelic Acids" Chemistry Letters. 21-24 (1993)
[Publications] M.Horikawa: "Efficient Syntheses of Acromelic Acids B and E Which Are Potent Neuroexcitatory Amino Acids" Tetrahidron Letters. 34. 331-334 (1993)
[Publications] M.Tanaka: "Chirality of the Acyl Group of Gymnopilin" Phytochemistry. 31. 4355-4356 (1992)
[Publications] K.Hashimoto: "Configurational Variants of Hydroxyphenylkainoids:Their Potent Depolarizing Activities in the Rat Central Nervous System" Bioorganic Medicinal Chemistry Letters. 2. 743-746 (1992)
[Publications] S.Kwak: "Acromelic acid,a novel kainate analogue,induces long-lasting paraparesis with selective degeneration of interneurons in the rat spinal cord" Exp.Neurol.116. 145-155 (1992)
[Publications] S.Kwak: "New Potent kainate derivatives:comparison of their affinity for [ ^3H] kainate and [ ^3H] AMPA binding sites" Neurosci,Lett.139. 114-117 (1992)
[Publications] K.Hashimoto: "Configurational variants of hydroxyphenylkainoids:Their potent depolarizing activities in the rat central vervous system" Bioorg.Med.Chem.Lett.2. 743-746 (1992)
[Publications] H.Shinozaki: "A metabotropic L-glutamate receptor agonist:pharmacological defference between rat central neurones and crayfish neuromuscular junctions" Comp.Biochem.Physiol.103C. 13-17 (1992)
[Publications] Y.Ohfune: "Synthesis of L-2-(2,3-dicarboxycyclopropyl)glycine:novel conformationally restricted glutamate analog" Bioorg.Med.Chem.Lett.3. 15-18 (1993)
[Publications] H.Shinozaki: "Excitatory amino acids:physiological and pharmacological probes for neuroscience probes for neuroscience research" Acta Neurobiol.Exp.(1993)
[Publications] N.Sakai: "Total Synthesis of Galantin I.Acid-Catalyzed Cyclization of Galantinic Acid" J.Am.Chem.Soc.114. 998-1010 (1992)
[Publications] M.Kawai: "2-(Carboxycyclopropyl)glycines:Binding,Neurotoxicity and Induction of Intracellular Free Ca^<2+> Increase" Eur.J.Phamacol. 211. 195-202 (1992)
[Publications] Y.Ohfune: "Design,Synthesis and Excitatory Activity of Conformationally Restricted L-Glutamate Analogues in the Mammalian Central Nervous System" Trends in Medicinal Chemistry'90. 175-182 (1992)
[Publications] Y.Ohfune: "Stereoselective Routes toward the Synthesis of Unusual Amino Acids" Acc.Chem.Res.25. 360-366 (1992)
[Publications] Y.Hayashi: "Agonist Analysis of 2-(Carboxycyclopropyl)glycine Isomers for Cloned Metabotropic Glutamate Recertor Subtypes Expressed in Chinese Hamster Ovary Cells" Br.J.Pharmacol.107. 536-543 (1992)
[Publications] 白濱晴久: "生物毒の世界" 大日本図書(株), 24 (1992)
[Publications] H.Shirahama: "Organic Synthesis in Japan Past,Present,and Future" Tokyo Kagaku Dozin, 12 (1992)
[Publications] H.Shinozaki: "Excitatory Amino Acids" Fidia Foundatuon, 9 (1992)
[Publications] H.Shinozaki: "Neuroreceptors,Ion Chennel and the Brain" Elsevier Science Publishers, 8 (1992)
[Publications] H.Shinozaki: "Excitatory amino acid receptors:desigb of agonists and antagonists" Ellis Horwood, 32 (1991)
[Publications] Y.Ohfune: "Drug design,molecular modeling and the neuroscience" Raven Press NY, 17 (1992)

1992 Fiscal Year Annual Research Report

神経伝達機構に作用する高度活性物質の開発

Principal Investigator

白濱 晴久 北海道大学, 理学部, 教授 (00000802)

Research Products

[Publications] M.Tanaka: "Neurotoxic Oligoisoprenoids of Hallucinogenic Mushroom,Gymnopilus spectabilis" Phytochemistry. 32. (1993)

[Publications] K.Yamano: "New Amino Acids from Clitocybe acromelalga.Possible Intermediates in the Biogenesis of Mushroom Toxins,Acromelic Acids" Tetrahedron. 49. (1993)

[Publications] K.Yamano: "Isolation of L-N-[2-(3-Pyridyl)ethyl]-glutamic Acid from the Poisonous Mushroom Clitocybe acromelalga.A Possible Intermediate in the Biogenes is of Acromelic Acids" Chemistry Letters. 21-24 (1993)

[Publications] M.Horikawa: "Efficient Syntheses of Acromelic Acids B and E Which Are Potent Neuroexcitatory Amino Acids" Tetrahidron Letters. 34. 331-334 (1993)

[Publications] M.Tanaka: "Chirality of the Acyl Group of Gymnopilin" Phytochemistry. 31. 4355-4356 (1992)

[Publications] K.Hashimoto: "Configurational Variants of Hydroxyphenylkainoids:Their Potent Depolarizing Activities in the Rat Central Nervous System" Bioorganic Medicinal Chemistry Letters. 2. 743-746 (1992)

[Publications] S.Kwak: "Acromelic acid,a novel kainate analogue,induces long-lasting paraparesis with selective degeneration of interneurons in the rat spinal cord" Exp.Neurol.116. 145-155 (1992)

[Publications] S.Kwak: "New Potent kainate derivatives:comparison of their affinity for [ ^3H] kainate and [ ^3H] AMPA binding sites" Neurosci,Lett.139. 114-117 (1992)

[Publications] K.Hashimoto: "Configurational variants of hydroxyphenylkainoids:Their potent depolarizing activities in the rat central vervous system" Bioorg.Med.Chem.Lett.2. 743-746 (1992)

[Publications] H.Shinozaki: "A metabotropic L-glutamate receptor agonist:pharmacological defference between rat central neurones and crayfish neuromuscular junctions" Comp.Biochem.Physiol.103C. 13-17 (1992)

[Publications] Y.Ohfune: "Synthesis of L-2-(2,3-dicarboxycyclopropyl)glycine:novel conformationally restricted glutamate analog" Bioorg.Med.Chem.Lett.3. 15-18 (1993)

[Publications] H.Shinozaki: "Excitatory amino acids:physiological and pharmacological probes for neuroscience probes for neuroscience research" Acta Neurobiol.Exp.(1993)

[Publications] N.Sakai: "Total Synthesis of Galantin I.Acid-Catalyzed Cyclization of Galantinic Acid" J.Am.Chem.Soc.114. 998-1010 (1992)

[Publications] M.Kawai: "2-(Carboxycyclopropyl)glycines:Binding,Neurotoxicity and Induction of Intracellular Free Ca^<2+> Increase" Eur.J.Phamacol. 211. 195-202 (1992)

[Publications] Y.Ohfune: "Design,Synthesis and Excitatory Activity of Conformationally Restricted L-Glutamate Analogues in the Mammalian Central Nervous System" Trends in Medicinal Chemistry'90. 175-182 (1992)

[Publications] Y.Ohfune: "Stereoselective Routes toward the Synthesis of Unusual Amino Acids" Acc.Chem.Res.25. 360-366 (1992)

[Publications] Y.Hayashi: "Agonist Analysis of 2-(Carboxycyclopropyl)glycine Isomers for Cloned Metabotropic Glutamate Recertor Subtypes Expressed in Chinese Hamster Ovary Cells" Br.J.Pharmacol.107. 536-543 (1992)

[Publications] 白濱 晴久: "生物毒の世界" 大日本図書(株), 24 (1992)

[Publications] H.Shirahama: "Organic Synthesis in Japan Past,Present,and Future" Tokyo Kagaku Dozin, 12 (1992)

[Publications] H.Shinozaki: "Excitatory Amino Acids" Fidia Foundatuon, 9 (1992)

[Publications] H.Shinozaki: "Neuroreceptors,Ion Chennel and the Brain" Elsevier Science Publishers, 8 (1992)

[Publications] H.Shinozaki: "Excitatory amino acid receptors:desigb of agonists and antagonists" Ellis Horwood, 32 (1991)

[Publications] Y.Ohfune: "Drug design,molecular modeling and the neuroscience" Raven Press NY, 17 (1992)

白濱晴久北海道大学, 理学部, 教授 (00000802)

[Publications] 白濱晴久: "生物毒の世界" 大日本図書(株), 24 (1992)