DESIGN AND SYNTHESIS OF THE OPIOID RECEPTOR PROBE
| Project/Area Number |
05453185
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| Research Category |
Grant-in-Aid for General Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Research Field |
医薬分子機能学
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
KANEMATSU Ken KYUSHU UNIVERSITY FACULTY OF PHARMACEUTICAL SCIENCES,PROFESSOR, 薬学部, 教授 (70023041)
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| Project Period (FY) |
1993 – 1995
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| Project Status |
Completed (Fiscal Year 1995)
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| Budget Amount *help |
¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 1995: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1994: ¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1993: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | Opioid / Opioid Receptor / Ligand / Morphine / Affinity Labeling / 3D Model / Cystein Residue / システイン残基 / 二酸化セレン / アミノ酸配列 / 10-ケトモルヒネ |
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| Research Abstract |
For three-dimensional understanding of the mechanisms that control potency and selectivity of the ligand binding at the atomic level, we have analyzed the feature of the opioid receptor-ligand interaction based on the receptor's 3D model. As the first step, we have constructed molecular models for the multiple opioid receptor subtypes by using bacteriorhodopsin as a template. The S-activated dihydromorphine derivatives should serve as powerful tools in mapping mu receptor three dimensional structure, including the nature of the agonist-mediated conformational change that permits G protein-coupling to "second messenger" effector molecules, and in identifying specific ligand-binding contacts with the mu opioid receptor. The analyzes of the interactions of some opioid ligands with the predicted ligand binding sites are consistent with the results of the affinity labeling experiments.
Two S-Activated sulfhydryldihydrylmorphine analogs were synthesized. In the rat brain receptor binding assays, both compounds exhibited considerably high affinities for mu opioid receptors (IC_<50> ; 10.7,31.1 nM). However, when each analog was incubated with membranes for the purpose of getting disulfide bridgings, one (EC_<50>=58nM) was found to affinity-label the mu receptors about 30 times more effectively than the other (EC_<50>=1700nM).
The design and synthesis of 10-oxo derivative of N-cycloprorylmethyl- (-) -6beta-acetylthio-dihydronormorphine are achieved. The result of pharmacological assays indicate that compound acts as a mu opioid receptor antagonist and k opioid receptor agonist which is suggested to be more potent analgesic action than that of N-cycloprorylmethyl- (-) -6beta-acetylthiodihydronormorphine and morphine through an activation of k opioid receptors.
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Report
(4 results)
Research Products
(10 results)
