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[摘要]：Conformational restraint in the N-substituent of enantiomeric 5-(3-hydroxyphenyl)morphans was conferred by the addition of a cyclopropane ring or a double bond. All of the possible enantiomers and isomers of the N-substituted compounds were synthesized. Opioid receptor binding assays indicated that some of them had about 20-fold higher mu-affinity than the compound with an N-phenylpropyl substituent (K-i = 2-450 nM for the examined compounds with various N-substituents). Most of the compounds acted unusually as inverse agonists in the [S-35]GTP-gamma-S functional binding assay using nondependent cells that stably express the cloned human mu-opioid receptor. Two of the N-substituted compounds with a cyclopropane ring were very potent mu-opioid antagonists ((+)-29, K-e = 0.17 and (-)-30, K-e = 0.3) in the [S-35]GTP-gamma-S functional binding assay. By comparison of the geometry-optimized structures of the newly synthesized compounds, an attempt was made to rationalize their mu-opioid receptor affinity in terms of the spatial position of N-substituents. |
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