Decker Michael, Fulton Brian S, Zhang Bin, Knapp Brian I, Bidlack Jean M, Neumeyer John L
Alcohol & Drug Abuse Research Center, McLean Hospital, Harvard Medical School, 115 Mill Street, Belmont, Massachusetts 02478-9106, USA.
J Med Chem. 2009 Dec 10;52(23):7389-96. doi: 10.1021/jm900379p.
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 micro receptors in the [(35)S]GTPgammaS binding assay.
合成了含有酯连接体的二价吗啡喃化合物，并测定了它们对μ、δ和κ阿片受体的结合亲和力。在对水解不稳定的酯键相邻位置添加甲基可提高稳定性，同时仅部分影响结合亲和力。所得具有优化间隔长度和结构的二价配体显示出强效的结合谱，其中最有效的化合物（4b）对μ和κ阿片受体的K(i)值均为0.47 nM，而化合物4a对μ和κ受体的K(i)值分别为0.95 nM和0.62 nM。在[(35)S]GTPγS结合试验中，4a和4b在κ和μ受体上均为部分激动剂。
