Univalent and Bivalent Ligands of Butorphan: Characteristics of the Linking Chain Determine the Affinity and Potency of Such Opioid Ligands
Univalent and Bivalent Ligands of Butorphan: Characteristics of the Linking Chain Determine the Affinity and Potency of Such Opioid Ligands
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DOI：
10.1021/jm900379p
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发表时间：
2009-12-10
影响因子：
7.3
通讯作者：
Neumeyer, John L.
中科院分区：
文献类型：
--
作者：
Decker, Michael;Fulton, Brian S.;Neumeyer, John L.
合成了含酯连接物的二价吗啡类化合物，并测定了它们在µ、Delta和kappa阿片受体上的结合亲和力。在不易水解的酯键附近添加甲基增加了稳定性，但仅部分影响结合亲和力。得到的具有优化间隔区长度和结构的二价配体显示出与最有效的化合物(4b)和4a的有效结合谱，其中u和kappa阿片受体的K-I值均为0.47 nM，u和kappa受体的K-I值分别为0.95和0.62 nM。在[S-35]GTP-γS结合实验中，4a和4b都是kappa和u受体的部分激动剂。
Bivalent morphinan compounds containing ester linkers were synthesized and their binding affinities at the mu, delta, and kappa opioid receptors determined. Addition of methyl groups adjacent to the hydrolytically labile ester linkage increased stability while only partially affecting binding affinity. The resulting bivalent ligands with optimized spacer length and structure show potent binding profiles with the most potent compound (4b), having K-i values of 0.47 nM for both the mu and kappa opioid receptors, and 4a, having K-i values of 0.95 and 0.62 nM for the mu and kappa receptors, respectively. Both 4a and 4b were partial agonists at the kappa and mu receptors in the [S-35]GTP gamma S binding assay.