Department of Pharmaceutical Sciences, Wayne State University, 259 Mack Avenue, Detroit, MI 48202, USA.
ChemMedChem. 2012 Dec;7(12):2093-100. doi: 10.1002/cmdc.201200352. Epub 2012 Oct 11.
To further explore the basic structural motifs (3S,6S)-6-benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine and (2S,4R,5R)-2-benzhydryl-5-(benzylamino)tetrahydro-2H-pyran-4-ol, developed by our research group, for monoamine transport inhibition, we designed and synthesized various structurally altered analogues. The new compounds were tested for their affinities for the dopamine transporter (DAT), the serotonin transporter (SERT), and the norepinephrine transporter (NET) in rat brain by measuring their capacity to inhibit the uptake of [(3)H]DA, [(3)H]5-HT, and [(3)H]NE, respectively. Our results point to novel compounds with a TUI, DNRI, SNRI, or SSRI profile. Among the TUIs, compound 2 g exhibited a balanced potency for all three monoamine transporters (K(i): 60, 79, and 70.3 nM for DAT, SERT, and NET, respectively). In the rat forced swim test, compound 2 g produced a significant decrease in immobility in drug-treated rats relative to vehicle, indicating a potential antidepressant property.
为了进一步探索我们研究小组开发的基本结构基序（3S，6S）-6-苯并基-N-苄基四氢-2H-吡喃-3-胺和（2S，4R，5R）-2-苯并基-5-（苄基氨基）四氢-2H-吡喃-4-醇对单胺转运抑制的作用，我们设计并合成了各种结构改变的类似物。通过测量它们抑制[（3）H] DA，[（3）H] 5-HT和[（3）H] NE摄取的能力，分别在大鼠脑中测试了新化合物对多巴胺转运体（DAT），5-羟色胺转运体（SERT）和去甲肾上腺素转运体（NET）的亲和力。我们的结果指向具有 TUI，DNRI，SNRI 或 SSRI 特征的新型化合物。在 TUI 中，化合物 2 g 对所有三种单胺转运体（DAT，SERT 和 NET 的 Ki：60、79 和 70.3 nM）均表现出平衡的效力。在大鼠强迫游泳试验中，与载体相比，化合物 2 g 在药物处理的大鼠中显着减少了不动性，表明其具有潜在的抗抑郁特性。
