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1991 Fiscal Year Final Research Report Summary

Drug Design and Development of Glutamate Blockers which protect against Neuronal Death.

Research Project

Project/Area Number 02557104
Research Category

Grant-in-Aid for Developmental Scientific Research (B)

Allocation TypeSingle-year Grants
Research Field 応用薬理学・医療系薬学
Research InstitutionThe Tokyo Metropolitan Institute of Medical Science

Principal Investigator

SHINOZAKI Haruhiko  The Tokyo Metropolitan Institute of Medical Science, Pharmacology, Head Researcher, 薬理, 研究員 (20109945)

Co-Investigator(Kenkyū-buntansha) ISHIDA Michiko  The Tokyo Metropolitan Institute of medical Science, Researcher, 東京都臨床医学総合研究所・薬理, 研究員 (90124437)
KWAK Shin  National Institute of Neuroscience Researcher, 神経研究所, 室長 (40160981)
OHFUNE Yasufumi  Suntory Institute of Bioorganic Research, Researcher, サントリー生物有機科学研究所, 研究員 (20142078)
SHINOZAKI Haruhiko  The Tokyo Metropolitan Institute of Medical Science, Pharmacology, Head Research (20109945)
Project Period (FY) 1990 – 1991
KeywordsGlutamate / Metabotropic glutamate receptor / presynaptic inhibition / monosynaptic reflex / Neuron damage / NMDA antagonist
Research Abstract

L-CCG-I, a potent metabotropic glutamate receptor agonist, potentiated markedly the presynaptic inhibition in the isolated newborn rat spinal cord preparation, preferentially depressing monosynaptic reflexes induced by electrical stimulation of the dorsal root fibres. The depression of monosynaptic reflexes by L-CCG-I was caused in concentrations wen below those which did not cause postsynaptic depolarization. This inhibitory action of L-CCG-I is somewhat different from that of trans-ACPD, another metabotropic glutamate receptor agonist. The inhibitory action of L-CCG-I is not depressed by any known pharmacological agents. When this drug was asministered into the ventricule, generalized muscle relaxtant actions were observed in the rat. When L-CCG-L and trans-ACPD were injected into the lateral ventricule, cortex, and hippocampus, they did not induce neuronal damage in these areas. In the mongolian gerbil, ischemic neuronal damage was considerably blocked by pretreatmefnt with intraventricular L-CCG I. These experimental data suggest that the metabotropic glutamate receptor agonist may be useful for the prevention of neuronal damage.
An interesting compound has been succeeded in, synthesis by a group of the Tohoku University. This compound has been knwon as an endogenous one, but the pharmacological and physiological actions have been unknown. This compound demonstrated to be a considerably potent NMDA antagonist, and its activity was about 20 times lower than that of CPP. However, NMDA receptors have been believed to be related to neuronal death induced by excitatory amino acids, therefore, it is of great interest to examine the physiological function of this compound in the body.

  • Research Products

    (38 results)

All Other

All Publications (38 results)

  • [Publications] M.Ishida,Y.ohfune,Y.Shimada,K.Shimamoto,H.Shinozaki: "Changes in preference for receptor subtypes of conformational variants of a glutamate analog:conversion from the NMDA-type to the non-NMDA type." Brain Research. 550. 152-156 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] K.Shimamoto,M.Ishida,H.Shinozaki,Y.Ohfune,: "Synthesis of four diastereomeric L-2-(carboxycyclopropyl)glycines.Conformationally constrained L-glutamate analogues." J.Org.Chem.56. 4167-4176 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.kwak,H.Aizawa,M.Ishida,H.Shinozaki: "Systemic administration of acromelic acid induces selective neuron damage in the rat spinal cord." Life Sci.49. 91-96 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Ishida,H.Shinozaki: "Novel Kainate derivatives:potent depolarizing actions on spinal motoneurones and dorsal root fibres in newborn rats." Brit.J.Pharmacol.104. 873-878 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.kudo,K.Akita,M.Ishida,H.Shinozaki: "A significant increase in intracellular Ca_2^+ concentration induced by (2S,3R,4S)-2-(carboxy-cyclopropyl)glycine,a new potent NMDA agonist,in cultured rat hippocampal neurons." Brain Research. 567. 342-345 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] S.Kwak,H.Aizawa,M.Ishida,H.Shinozaki: "Acromelic acid,a novel kainate analogue,induces longlasting paraparesis with selective degeneration of interneurons in the rat spinal cord." Exp.Neurol.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Shinozaki and M.Ishida: "A metabotropic L-glutamate receptor agonist:Pharmacological difference between rat central neurones and crayfish neuromuscular junction." Comp.Physiol.Pharmacol.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 篠崎 温彦: "興奮性アミノ酸レセプタ-と植物由来神経毒" 神経研究の進歩. 35. 600-612 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Y.Nakagawa,T.saitoh,T.Ishihara,M.Ishida and H.shinozaki: "(2S,3S,4S)-α-(Carboxycyclopropyl)glycine is a novel agonist of metabotropic glutamate receptprs." Eur.J.Pharmacol.184. 205-206 (1990)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Ishida,H.Akagi,J.Shimamoto,Y.Ohfune and H.Shinozaki: "A potent metabotropic glutamate receptor agonist:Electrophysio-logical actions of a conformationally restricted glutamate analogue in the tat spinal cord and Xenopus oocytes." Brain Res.537. 311-314 (1990)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Kawai,Y.Horikawa,T.Ishihara,K.Shimamoto and Y.Ohfune: "2-(Carboxycyclopropyl)glycine.binding,neurotoxicity and induction of intracellular free Ca2+ increase." Eur.J.Pharmacol.211. 293-316 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 篠崎 温彦: "興奮性アミノ酸と神経細胞死" Brain Med.2. 63-69 (1990)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 郭 伸: "アクロメリン酸による脊髄ニュ-ロンの選択的神経細胞死" 脊髄神経疾患の動物モデル、医学の歩み. 159. 4167-4176 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 石田 美知子,篠崎 温彦: "神経系に作用する薬物マニュアル:オ-プンチャネル" 生体の科学. 142. 416-417 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Shinozaki,M.Ishida: "Recent advances in the study of glutamate receptor agonists." Asia Pacific J.Pharmacol.6. 293-316 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 篠崎 温彦: "興奮性アミノ酸レセプタ-の中枢薬理" 薬物・精神・行動.

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 石田 美知子,篠崎 温彦: "続医薬品講座" 広川書店,

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Shinozaki: "Excitatory Amino Acids" Thieme, 292 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Shinozaki and M.Ishida: "Neuroreceptor" Elsevier,

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Shinozaki,M.Ishida,Y,Kudo: "NMDA receptor related agents:Biochemistry,pharmacology and behavior" NPP Books, 414 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Shinozaki,M.Ishida,S.Kwak and T.Nakajima: "Method in Neuroscience" Academic Press, 496 (1991)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Sinozaki: "Excitatory Amino Acid Receptors" Ellis Horwood,

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] H.Shinozaki,M.Ishida,Y.Gotoh and S.Kwak: "Maturation Phenomena" springer-Verlag.,

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 石田 美知子,篠崎 温彦: "Annual Review 神経1992" 中外医学社, 360 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 郭 伸: "Annual Review 神経1992" 中外医学社, 360 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 篠崎 温彦: "続医薬品の開発、第10巻「海洋資源と医薬品」" 広川書店, 548 (1992)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] Shinozaki H., Ishida M. and Gotoh Y.: "Selective N-methyl-D-aspartate (NMDA) antagonists increase gastric motility in the rat." Neurosci. Lett.113. 56-61 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Nakagawa Y., Saitoh T., Ishihara T., Ishida M. and Shinozaki H.: "(2S, 3S, 4S)-alpha-(Carboxycyclopropyl) glycine is a novel agonist of metabotropic glutamate receptors." Eur. J. Pharmacol.184. 205-206 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishida M., Akagi H., Shimamoto J., Ohfune Y. and Shinozaki H.: "A potent metabotropic glutamate receptor agonist : Electro-physiological actions of a conformationally restricted glutamatea nalogue in the rat spinal cord and Xenopus oocytes." Brain Res.537. 311-314 (1990)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Simamoto, K., Ishida, M., Shinozaki, H. and Ohfune Y.: "Synthesis of four Diastereomeric L-2-(Carboxycyclopropyl) glycines. Conformationally Constrained L-Glutamate Analogues." J. Org. Chem.56. 4167-4176 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishida, M., Ohfune, Y., Shimada, Y., Shimamoto, K., Shinozaki, H.: "Changes in preference for receptor subtypes of conformational variants of a glutamate analog : conversion from the NMDA-type to the non-NMDA type." Brain Research. 550. 152-156 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kwak, S., Aizawa, H., Ishida, M., Shinozaki, H.: "Systemic administration of acromelic acid induces selective neuron damage in the rat spinal cord." Life Sci.49. PL-91-96 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Ishida, M., Shinozaki, H.: "Novel kainate derivatives : potent depolarizing actions on spinal motoneurones and dorsal root fibres in newborn rats." Brit. J. Pharmacol.104. 873-878 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinozaki, H., Ishida, M.: "Recent advances in the study of glutamate receptor agonists." Asia Pacific J. Pharmacol.6. 293-316 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kudo, Y., Akita, K., Ishida, M., Shinozaki, H.: "A significant increase in intracellular Ca2+ concentration induced by (2S, 3R, 4S) 2-(carboxy-cyclopropyl) glycine, a new potent NMDA agonist, in cultured rat hippocampal neurons." Brain Research. 567. 342-345 (1991)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Kawai, M., Horikawa, Y., Ishihara, T., Shimamoto, K. and Ohfune, Y.: "2-(Carboxycyclopropyl) glycine. binding, neurotoxicity and induction of intracellular free Ca2+ increase." Eur. J. Pharmacol. 211. 195-202 (1992)

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] KwaK, S., Aizawa, H., Ishida, M., Shinozaki, H.: "Acromelic acid, a novel kainate analogue, induces long-lasting paraparesis with selective degeneration of interneurons in the rat spinal cord." Exp. Neurol.

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] Shinozaki, H. and Ishida, M.: "A metabotropic L-glutamate receptor agonist : Pharmacological difference between rat central neurones and crayfish neuromuscular junction." Comp. Physiol. Pharmacol.

    • Description
      「研究成果報告書概要(欧文)」より

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Published: 1993-03-16  

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