Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression.
Optimization of a small tropomyosin-related kinase B (TrkB) agonist 7,8-dihydroxyflavone active in mouse models of depression.
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DOI：
10.1021/jm301099x
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发表时间：
2012-10-11
影响因子：
7.3
通讯作者：
Ye, Keqiang
中科院分区：
文献类型：
--
作者：
Liu, Xia;Chan, Chi-Bun;Qi, Qi;Xiao, Ge;Luo, Hongbo R.;He, Xiaolin;Ye, Keqiang
构效关系研究表明，选择性TrkB受体激动剂7，8-二羟基黄酮中的邻苯二酚基团是该受体激动剂活性的关键。为了改善儿茶酚分子固有的不良药代动力学特征，提高先导化合物的激动剂效应，我们通过合成各种生物等构体衍生物发起了先导化合物的优化运动。在这里，我们证明优化的2-methyl-8-(4′-(pyrrolidin-1-yl)phenyl)chromeno[7，8-d]imidazol-6(1H)-one衍生物具有增强的TrkB刺激活性。长期口服该化合物可显著降低两种经典抗抑郁动物模型-强迫游泳实验和悬尾实验中的不动，并伴随着小鼠脑内海马区TrkB的强烈激活。此外，体外ADMET研究表明，与以前的先导化合物相比，该化合物具有更好的特性。因此，这种优化的化合物可能成为治疗包括抑郁症在内的各种神经疾病的深度药物开发的有前途的候选药物。
Structure-activity relationship study shows that the catechol group in 7,8-dihdyroxyflavone, a selective small TrkB receptor agonist, is critical for the agonistic activity. To improve the poor pharmacokinetic profiles intrinsic to catechol-containing molecules and elevate the agonistic effect of the lead compound, we initiated the lead optimization campaign by synthesizing various bioisosteric derivatives. Here we show that the optimized 2-methyl-8-(4′-(pyrrolidin-1-yl)phenyl)chromeno[7,8-d]imidazol-6(1H)-one derivative possesses the enhanced TrkB stimulatory activity. Chronic oral administration of this compound significantly reduces the immobility in forced swim test and tail suspension test, two classical antidepressant behavioral animal models, which is accompanied by robust TrkB activation in hippocampus of mouse brain. Further, in vitro ADMET studies demonstrate that this compound possesses the improved features compared to the previous lead compound. Hence, this optimized compound may act as a promising lead candidate for in-depth drug development for treating various neurological disorders including depression.
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影响因子：
3.7
作者：
Jang SW;Liu X;Chan CB;France SA;Sayeed I;Tang W;Lin X;Xiao G;Andero R;Chang Q;Ressler KJ;Ye K
通讯作者：
Ye K
影响因子：
14.9
作者：
Chang DT;Oyang YJ;Lin JH
通讯作者：
Lin JH
影响因子：
5.3
作者：
Blugeot, Aurelie;Rivat, Cyril;Becker, Chrystel
通讯作者：
Becker, Chrystel
影响因子：
7.6
作者：
Devi, Latha;Ohno, Masuo
通讯作者：
Ohno, Masuo
DOI：
10.1073/pnas.0402141101
发表时间：
2004-07-20
影响因子：
11.1
作者：
Monteggia, LM;Barrot, M;Nestler, EJ
通讯作者：
Nestler, EJ