Flexible and biomimetic analogs of triple uptake inhibitor 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: Synthesis, biological characterization, and development of a pharmacophore model.
Flexible and biomimetic analogs of triple uptake inhibitor 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: Synthesis, biological characterization, and development of a pharmacophore model.
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DOI：
10.1016/j.bmc.2013.11.017
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发表时间：
2014-01-01
影响因子：
3.5
通讯作者：
Dutta A
中科院分区：
文献类型：
--
作者：
Sharma H;Santra S;Debnath J;Antonio T;Reith M;Dutta A
在这项研究中，我们已经产生了一个药效团模型的三重摄取抑制剂化合物的基础上，新的不对称吡喃衍生物和新开发的不对称呋喃衍生物。该模型揭示了抑制剂对多巴胺转运蛋白（DAT）、5-羟色胺转运蛋白（SERT）和去甲肾上腺素转运蛋白（NET）表现出平衡活性的重要特征。特别是，“折叠”构象被发现常见的活性吡喃化合物的训练集，是至关重要的三重摄取抑制活性。此外，二苯甲基部分和N-苄基之间的距离以及仲氮的取向对TUI活性也很重要。我们通过合成和测试新型不对称吡喃类似物来验证我们的发现。目前的工作也导致了一系列新的不对称四氢呋喃衍生物作为新的TUI的发现。先导化合物41和42表现出中等的TUI活性。有趣的是，四氢呋喃先导化合物（例如41和42）的最高TUI活性表现为与吡喃TUI（例如D-161）类似的立体化学偏好。
In this study we have generated a pharmacophore model of triple uptake inhibitor compounds based on novel asymmetric pyran derivatives and the newly developed asymmetric furan derivatives. The model revealed features important for inhibitors to exhibit a balanced activity against dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET). In particular, a ‘folded’ conformation was found common to the active pyran compounds in the training set and was crucial to triple uptake inhibitory activity. Furthermore, the distances between the benzhydryl moiety and the N-benzyl group as well as the orientation of the secondary nitrogen were also important for TUI activity. We have validated our findings by synthesizing and testing novel asymmetric pyran analogs. The present work has also resulted in the discovery of a new series of asymmetric tetrahydrofuran derivatives as novel TUIs. Lead compounds 41 and 42 exhibited moderate TUI activity. Interestingly, the highest TUI activity by lead tetrahydrofuran compounds e.g. 41 and 42, was exhibited in a stereochemical preference similar to pyran TUI e.g. D-161.
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影响因子：
7.3
作者：
Gopishetty, Bhaskar;Hazeldine, Stuart;Santra, Soumava;Johnson, Mark;Modi, Gyan;Ali, Solav;Zhen, Juan;Reith, Maarten;Dutta, Aloke
通讯作者：
Dutta, Aloke
影响因子：
--
作者：
Gopishetty, Bhaskar;Gogoi, Sanjib;Dutta, Aloke K.
通讯作者：
Dutta, Aloke K.
影响因子：
5
作者：
Dutta, Aloke K.;Ghosh, Balaram;Reith, Maarten E. A.
通讯作者：
Reith, Maarten E. A.
影响因子：
7.4
作者：
Casper, R C
通讯作者：
Casper, R C
影响因子：
2.2
作者：
Pandit, Deepangi;Roosma, William;Venanzi, Carol A.
通讯作者：
Venanzi, Carol A.