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1989 Fiscal Year Final Research Report Summary

Molecular Design of delta-Selective Morphine Dimer Based on Enkephalin Conformation

Research Project

Project/Area Number 63571029
Research Category

Grant-in-Aid for General Scientific Research (C)

Allocation TypeSingle-year Grants
Research Field Physical pharmacy
Research InstitutionOsaka University of Pharmaceutical Sciences

Principal Investigator

ISHIDA Toshimasa  Osaka University of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00111021)

Project Period (FY) 1988 – 1989
KeywordsMorphine Dimer / Opioid Receptor / mu / delta-Receptor Selectivity / Molecular Conformation / 構造活性相関
Research Abstract

1. Chemical Syntheses of a Series of Morphine Dimers
Based on the possible relationship between the molecular conformations of enkephalin and the binding to mu/delta-opioid receptor, an attempt io structurally convert the mu-selective morphine molecule toward delta-selectivity was carried out by a series of morphine dimerizations. A series of morphine dimers in which the nitrogen atoms of two morphine molecules are linked by the -(CH_2)_n- [n= 0 - 6] linkage were chemically synthesized, and their physicochemical properties were elucidated by the spectroscopic method such as ^1H-NMR.
2. Pharmacological Measurements of a Series of Morphine Dimers
Pharmacologic activities of a series of morphine dimers were evaluated for the inhibitory effect on contraction of mouse isolated vas deferens and for the binding assay in homogenates of rat brain. The morphine dimer of n=2 exhibited the agonist activity showing about 15 timer more delta-selectivity than the parent morphine molecule, while that of n=3 showed a noticeable antagonist activity for mu/delta-receptor. The dimers of n 4 showed no significant pharmacological activities. The preference of n=2 dimer toward delta-receptor binding and the pharmacological difference between dimers of n=2 and 3 is an important information for considering the substrate specificity of mu/delta-opioid receptor.
3. Relationship between the Stable Conformations of Morphine Dimers of n=3 and 3 and the Binding to delta-opioid Receptor
The energetically stable conformations of morphine dimers of n=2 and 3 were investigated by the quantum chemical MNDO method. As a result, it was suggested as the most stable con- formations the extended planar form for n=2 dimer in which two morphine chromophores are almost related to each other with a C2-symmetry and the folded form without showing C2-symm- etry for n=3 dimer. This result clearly shows the preference of extended C2-symmetric conformation of opioid for the binding with delta-receptor.

  • Research Products

    (12 results)

All Other

All Publications (12 results)

  • [Publications] 土井光暢: "Conformational characteristics of receptor-selective opioid peptides ^1H-n.m.r and c.d. spectroscopic studies of delta-kephalin and (Val^4)morphiceptin" Biochem.J.251. 581-588 (1988)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 石田寿昌: "Molecular-dynamics simulations of(Met^5)-and(D-Ala^2,Met^5)-enkephalins:Biological implications of monomeric folded and dimeric unfolded conformations" Biochem.J.255. 621-628 (1988)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 米田茂隆: "Importance of folded monomer and extended antiparallel dimer structures as enkephalin active conformation:Molecular-dynamics simulations of(Met^5)enkephalin in water" FEBS Lett.239. 271-275 (1988)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 土井光暢: "Effects of thioamide substitution for the enkephalin conformation:Crystal structure of Boc-Tyr-Gly-Gly-Pheψ(CSNH)Leu-OBzl" Int.J.Peptide Protein Res.34. 369-373 (1989)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 屋良肇: "An attempt for structurally convert mu-selective morphine toward delta-receptor binding:Dimerization based on enkephalin conformation." Eur.J.Pharmacol.(1990)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] 石田寿昌: "エンケファリンの立体構造に基づくμ/δーオピオイドレセプタ-の基質特異性" 生物物理. (1990)

    • Description
      「研究成果報告書概要(和文)」より
  • [Publications] M.Doi, M.Tanaka, K.Ikuma, M.Nabae, K.Kitamura, M.Inoue and T.Ishida: "Conformational characteristics of receptor-selective opioid peptides: ^1H-n.m.r and c.d. spectroscopic studies of delta- kephalin and [Val^4]morphiceptin" Biochem.J. 251, 581-588 (1988).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T.Ishida, S.Yoneda, M.Doi, M.Inoue, and K.Kitamura: "Molecular-dynamics simulations of [Met^5]0 and [D-Ala^2,Met^5]-enkephalins: Biological implications of monomeric folded and dimeric unfolded conformations" Biochem.J. 255, 621-628 (1988).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] S.Yoneda, K.Kitamura, M.Doi, M.Inoue and T.Ishida: "Importance of folded monomer and extended antiparallel dimer structures as enkephalin active conformation: Molecular-dynamics simulations of [Met^5]enkephalin in water" FEBS Lett. 239, 271-275 (1988).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] M.Doi, S.Takehara, T.Ishida and M.Inoue: "Effects of thioamide substitution for the enkephalin conformation: Crystal structure of Boc-Gly-Gly-Phepsi[CSNH]Leu-OBzl" Int.J.Peptide Protein Res. 34, 369-373 (1989).

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] H.Yara, Y.Katagawa, M.Doi, T.Ishida, M.Inoue, M.Yasuda, A, Baba, H.Iwata, K.Kitamura and T.Sadatome: "An attempt to structurally convert mu-selective morphine toward delta-receptor binding: Dimerization based on enkephalin conformation" Eur.J.Pharmacol.

    • Description
      「研究成果報告書概要(欧文)」より
  • [Publications] T.Ishida and M.Doi: "Substrate specificity of mu/delta- opioid receptor based on enkephalin conformation" Biophysics.

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

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Published: 1993-03-26  

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