Structural exploration of (3S,6S)-6-benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine analogues: identification of potent triple monoamine reuptake inhibitors as potential antidepressants.
Structural exploration of (3S,6S)-6-benzhydryl-N-benzyltetrahydro-2H-pyran-3-amine analogues: identification of potent triple monoamine reuptake inhibitors as potential antidepressants.
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(3S,6S)-6-二苯甲基-N-苄基四氢-2H-吡喃-3-胺类似物的结构探索：鉴定有效的三元单胺再摄取抑制剂作为潜在的抗抑郁药。
DOI：
10.1002/cmdc.201200352
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发表时间：
2012
期刊：
影响因子：
3.4
通讯作者：
Dutta,AlokeK
中科院分区：
文献类型：
--
作者：
Santra,Soumava;Gogoi,Sanjib;Gopishetty,Bhaskar;Antonio,Tamara;Zhen,Juan;Reith,MaartenEA;Dutta,AlokeK
为了进一步探索本研究组开发的（3S，6S）-6-二苯甲基-N-苄基四氢-2H-吡喃-3-胺和（2S，4 R，5 R）-2-二苯甲基-5-（苄氨基）四氢-2H-吡喃-4-醇的基本结构基序用于单胺转运抑制，我们设计并合成了各种结构改变的类似物。通过测量新化合物分别抑制[3 H]DA、[3 H]5-HT和[3 H]NE摄取的能力，测试了它们对大鼠脑中多巴胺转运蛋白（DAT）、5-羟色胺转运蛋白（SERT）和去甲肾上腺素转运蛋白（NET）的亲和力。我们的研究结果指向具有TUI、DNRI、SNRI或SSRI特征的新型化合物。在TUI中，化合物2对所有三种单胺转运蛋白表现出平衡的效力（DAT、SERT和NET的Ki分别为60、79和70.3nM）。 在大鼠强迫游泳测试中，化合物2g相对于媒介物在药物处理的大鼠中产生不动性的显著降低，表明潜在的抗抑郁性质。
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 [3H]DA, [3H]5‐HT, and [3H]NE, respectively. Our results point to novel compounds with a TUI, DNRI, SNRI, or SSRI profile. Among the TUIs, compound2 gexhibited a balanced potency for all three monoamine transporters (Ki: 60, 79, and 70.3 nMfor DAT, SERT, and NET, respectively). In the rat forced swim test, compound2 gproduced a significant decrease in immobility in drug‐treated rats relative to vehicle, indicating a potential antidepressant property.