Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis.
Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis.
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DOI：
10.1021/jm400511s
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发表时间：
2013-06-27
影响因子：
7.3
通讯作者：
Kozikowski AP
中科院分区：
文献类型：
--
作者：
Gunosewoyo H;Midzak A;Gaisina IN;Sabath EV;Fedolak A;Hanania T;Brunner D;Papadopoulos V;Kozikowski AP
抑制葛兰素史克-3β已经被很好地证明解释了情绪稳定剂锂在各种情绪障碍动物模型中的行为行为。最近的研究表明，基因或药物抑制葛兰素史克-3β导致了类焦虑和亲社会行为。在我们正在努力开发用于治疗情绪障碍的葛兰素史克-3β抑制剂的过程中，我们对马来酰亚胺类化合物进行了合成孔径雷达研究。在此，我们首次报道了其中一些β抑制剂，特别是类似物1和9，能够在类固醇生成的MA-10小鼠肿瘤间质细胞模型中刺激孕酮的产生，而没有任何明显的毒性。这两种化合物在SmartCube®行为测试中进行了测试，在每日剂量(50 mg/kg，i.p.)后显示出类似于抗焦虑的特征。已经13天了。综上所述，这些结果支持这样的假设，即抑制葛兰素史克-3β可能会影响神经活性类固醇的产生，从而介导体内焦虑样行为的调节。
Inhibition of GSK-3β has been well documented to account for the behavioral actions of the mood stabilizer lithium in various animal models of mood disorders. Recent studies have showed that genetic or pharmacological inhibition of GSK-3β resulted in anxiolytic-like and pro-social behavior. In our ongoing efforts to develop GSK-3β inhibitors for the treatment of mood disorders, SAR studies on maleimide-based compounds were undertaken. We present herein for the first time that some of these GSK-3β inhibitors, in particular analogs 1 and 9, were able to stimulate progesterone production in the MA-10 mouse tumor Leydig cell model of steroidogenesis without any significant toxicity. These two compounds were tested in the SmartCube® behavioral assay and showed anxiolytic-like signatures following daily dose administration (50 mg/kg, i.p.) for 13 days. Taken together, these results support the hypothesis that GSK-3β inhibition could influence neuroactive steroid production thereby mediating the modulation of anxiety-like behavior in vivo.
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影响因子：
7.3
作者：
Fugel, Wiebke;Oberholzer, Anselm Erich;Kunick, Conrad
通讯作者：
Kunick, Conrad
影响因子：
7.6
作者：
Chiu, Chi-Tso;Liu, Guangping;Chuang, De-Maw
通讯作者：
Chuang, De-Maw
影响因子：
5
作者：
Chen, Po C.;Gaisina, Irina N.;Kozikowski, Alan P.
通讯作者：
Kozikowski, Alan P.
影响因子：
1.8
作者：
Faul, MM;Winneroski, LL;Krumrich, CA
通讯作者：
Krumrich, CA
影响因子：
--
作者：
Hauet, T;Yao, ZX;Papadopoulos, V
通讯作者：
Papadopoulos, V