Zeng Fanxing, Jarkas Nachwa, Owens Michael J, Kilts Clinton D, Nemeroff Charles B, Goodman Mark M
Department of Radiology, Division of Radiological Sciences, Emory University, Atlanta, GA 30322, USA.
Bioorg Med Chem Lett. 2006 Sep 1;16(17):4661-3. doi: 10.1016/j.bmcl.2006.05.098. Epub 2006 Jun 19.
A series of front bridged tricyclic 3beta-(4'-halo or 4'-methyl)phenyltropanes bearing methylene or carbomethoxymethylene on the bridge to the 2beta-position was synthesized, and their binding affinities were determined in cells transfected to express human norepinephrine transporter (NET), serotonin transporter (SERT), and dopamine transporter (DAT) via competition binding assays. All compounds studied in this series exhibit a moderate to high potency at all three transporters with SERT or DAT selectivity. 3beta-(4'-iodo)phenyltropane bearing methylene on the bridge to the 2beta-position (24) presents a particularly attractive pharmacological profile, with very high SERT affinity (K(i) = 0.09 nM) and selectivity versus NET (65-fold) and DAT (94-fold).
合成了一系列在与2β位相连的桥上带有亚甲基或甲氧基羰基亚甲基的前桥三环3β-(4'-卤代或4'-甲基)苯基托烷，并通过竞争结合试验在转染以表达人类去甲肾上腺素转运体（NET）、5-羟色胺转运体（SERT）和多巴胺转运体（DAT）的细胞中测定了它们的结合亲和力。该系列中研究的所有化合物在所有三种转运体上均表现出中等至高的效力，且具有SERT或DAT选择性。在与2β位相连的桥上带有亚甲基的3β-(4'-碘)苯基托烷（24）呈现出特别有吸引力的药理学特征，具有非常高的SERT亲和力（K(i)=0.09 nM）以及相对于NET（65倍）和DAT（94倍）的选择性。
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