| Project/Area Number |
63571029
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| Research Category |
Grant-in-Aid for General Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Research Field |
Physical pharmacy
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| Research Institution | Osaka University of Pharmaceutical Sciences |
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Principal Investigator |
ISHIDA Toshimasa Osaka University of Pharmaceutical Sciences, Professor, 薬学部, 教授 (00111021)
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| Project Period (FY) |
1988 – 1989
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| Project Status |
Completed (Fiscal Year 1989)
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| Budget Amount *help |
¥2,000,000 (Direct Cost: ¥2,000,000)
Fiscal Year 1989: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1988: ¥1,200,000 (Direct Cost: ¥1,200,000)
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| Keywords | Morphine Dimer / Opioid Receptor / mu / delta-Receptor Selectivity / Molecular Conformation / 構造活性相関 / μ@δ-レセプタ-選択性 / 分子コンフオメ-ション / エンケファリン / モルヒネ / モルヒネ二量体 / オピオイドレセプター / コンフォメーション |
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| 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.
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