Further structure-activity relationship studies on 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: identification of compounds with triple uptake inhibitory activity as potential antidepressant agents.
Further structure-activity relationship studies on 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol: identification of compounds with triple uptake inhibitory activity as potential antidepressant agents.
复制标题
DOI：
10.1021/jm200020a
复制
发表时间：
2011-04-28
影响因子：
7.3
通讯作者：
Dutta, Aloke
中科院分区：
文献类型：
--
作者：
Gopishetty, Bhaskar;Hazeldine, Stuart;Santra, Soumava;Johnson, Mark;Modi, Gyan;Ali, Solav;Zhen, Juan;Reith, Maarten;Dutta, Aloke
为了研究铅三重吸收抑制分子双取代4-((((3S，6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol，的结构变化，我们进行了结构-活性关系研究，考察了芳香族取代基的改变和杂环芳香基团的引入对该分子模板的影响。通过分别测定它们对[~3H]DA、[~H]5-HT和[~3H]NE摄取的抑制作用，测试了这些新化合物对脑内多巴胺转运体(DAT)、5-羟色胺转运体(SERT)和去甲肾上腺素转运体(NET)的亲和力。结果表明，噻吩衍生物(10g)和吡咯(10i)衍生物具有多巴胺去甲肾上腺素再摄取抑制(DNRI)型活性。另一方面，3-羟基苯基衍生物10f和4-甲氧基苯基衍生物10j对所有单胺转运体(Ki，分别为31.3，40，38.5和15.9，12.9，29.3，10f和10g)表现出三重再摄取抑制(TUI)活性。在大鼠强迫游泳实验中进一步评价化合物10f的抗抑郁作用。结果表明，TUI10f在10 mg/kg剂量下可显著降低小鼠的不动能力，提示其具有潜在的抗抑郁活性。
To investigate structural alterations of the lead triple uptake inhibitor molecule, disubstituted 4-((((3S,6S)-6-benzhydryltetrahydro-2H-pyran-3-yl)amino)methyl)phenol, we have carried out structure-activity relationship (SAR) studies to investigate the effect of alteration of aromatic substitutions and introduction of heterocyclic aromatic moieties on this molecular template. The novel compounds were tested for their affinities for the dopamine transporter (DAT), serotonin transporter (SERT), and norepinephrine transporter (NET) in the brain by measuring their potency in inhibiting the uptake of [3H]DA, [3H]5-HT, and [3H]NE, respectively. SAR results indicate dopamine norepinephrine reuptake inhibitory (DNRI) type activity in thiophene (10g) and pyrrole (10i) derivatives. On the other hand, 3-hydroxy phenyl derivative 10f and 4-methoxy phenyl derivative 10j exhibited a triple reuptake inhibitory (TUI) activity profile as these molecules exhibited potent uptake inhibition for all the monoamine transporters (Ki; 31.3, 40, 38.5 and 15.9, 12.9, 29.3 for DAT, SERT and NET, for 10f and 10g respectively). Compound 10f was further evaluated in the rat forced swim test to evaluate its potential antidepressant effect. The results show significant reduction of immobility by TUI 10f at 10 mg/kg dose, indicating potential antidepressant activity.
登录
查看更多内容
影响因子：
7.3
作者：
Kolhatkar, R;Cook, CD;Dutta, AK
通讯作者：
Dutta, AK
DOI：
10.1111/j.1527-3458.2006.00123.x
发表时间：
2006-06-01
期刊：
CNS DRUG REVIEWS
影响因子：
--
作者：
Skolnick, Phil;Krieter, Philip;Lippa, Arnold
通讯作者：
Lippa, Arnold
影响因子：
7.3
作者：
Ghorai, SK;Cook, C;Dutta, AK
通讯作者：
Dutta, AK
影响因子：
2.7
作者：
Dutta, AK;Davis, MC;Reith, MEA
通讯作者：
Reith, MEA
影响因子：
7.3
作者：
Dutta, AK;Davis, MC;Reith, MEA
通讯作者：
Reith, MEA