Béguin Cécile, Duncan Katharine K, Munro Thomas A, Ho Douglas M, Xu Wei, Liu-Chen Lee-Yuan, Carlezon William A, Cohen Bruce M
Mailman Research Center, McLean Hospital, Belmont, MA 02478, USA.
Bioorg Med Chem. 2009 Feb 1;17(3):1370-80. doi: 10.1016/j.bmc.2008.12.012. Epub 2008 Dec 14.
In an effort to find novel agents which selectively target the kappa opioid receptor (KOPR), we modified the furan ring of the highly potent and selective KOPR agonist salvinorin A. Introduction of small substituents at C-16 was well tolerated. 12-epi-Salvinorin A, synthesized in four steps from salvinorin A, was a selective partial agonist at the KOPR. No clear SAR patterns were observed for C-13 aryl ketones. Introducing a hydroxymethylene group between C-12 and the furan ring was tolerated. Small C-13 esters and ethers gave weak KOPR agonists, while all C-13 amides were inactive. Finally, substitution of oxadiazoles for the furan ring abolished affinity for the KOPR. None of the compounds displayed any KOPR antagonism or any affinity for mu or delta opioid receptors.
为了寻找选择性靶向κ阿片受体（KOPR）的新型药物，我们对强效且选择性的KOPR激动剂Salvinorin A的呋喃环进行了修饰。在C-16位引入小取代基具有良好的耐受性。从Salvinorin A经四步合成的12-表Salvinorin A是KOPR的选择性部分激动剂。对于C-13芳基酮，未观察到明确的构效关系模式。在C-12与呋喃环之间引入羟亚甲基是可以接受的。C-13位的小酯类和醚类产生较弱的KOPR激动剂，而所有C-13酰胺均无活性。最后，用恶二唑取代呋喃环消除了对KOPR的亲和力。这些化合物均未表现出任何KOPR拮抗作用或对μ或δ阿片受体的任何亲和力。
