Probes for Narcotic Receptor Mediated Phenomena. 41. Unusual Inverse μ-Agonists and Potent μ-Opioid Antagonists by Modification of the N-Substituent in Enantiomeric 5-(3-Hydroxyphenyl)morphans
Probes for Narcotic Receptor Mediated Phenomena. 41. Unusual Inverse μ-Agonists and Potent μ-Opioid Antagonists by Modification of the N-Substituent in Enantiomeric 5-(3-Hydroxyphenyl)morphans
复制标题
DOI：
10.1021/jm1011676
复制
发表时间：
2011-02-24
影响因子：
7.3
通讯作者：
Rice, Kenner C.
中科院分区：
文献类型：
--
作者：
Cheng, Kejun;Lee, Yong Sok;Rice, Kenner C.
对映体5-（3-羟基苯基）morphans的n取代基的构象约束是通过添加环丙烷环或双键来实现的。合成了所有可能的n -取代化合物的对映体和同分异构体。阿片受体结合实验表明，其中一些化合物的mu亲和力比含有n -苯丙基取代基的化合物高约20倍（对于含有各种n -取代基的化合物，K-i = 2-450 nM）。在[S-35] gtp - γ - s功能结合实验中，使用稳定表达克隆的人μ -阿片受体的非依赖性细胞，大多数化合物异常地作为逆激动剂。在[S-35] gtp - γ -s功能结合实验中，两个带有环丙烷环的n取代化合物是非常有效的μ -阿片拮抗剂(（+)-29,K-e = 0.17和(-)-30,K-e = 0.3）。通过对新合成化合物的几何优化结构进行比较，试图从n取代基的空间位置来合理化其对μ -阿片受体的亲和力。
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.