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首页> 外文期刊>Journal of Medicinal Chemistry >Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis
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Characterization of maleimide-based glycogen synthase kinase-3 (GSK-3) inhibitors as stimulators of steroidogenesis

机译：基于马来酰亚胺的糖原合酶激酶3（GSK-3）抑制剂作为类固醇生成刺激物的表征

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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 analogues 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, ip) 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.
机译：GSK-3β的抑制作用已得到充分证明，可以解释情绪稳定剂锂在各种情绪障碍动物模型中的行为作用。最近的研究表明，GSK-3β的遗传或药理抑制作用导致了抗焦虑样行为和亲社会行为。在我们不断开发用于治疗情绪障碍的GSK-3β抑制剂的努力中，对基于马来酰亚胺的化合物进行了SAR研究。我们在此首次提出这些GSK-3β抑制剂中的某些，特别是类似物1和9，能够在类固醇生成的MA-10小鼠肿瘤Leydig细胞模型中刺激孕酮产生，而没有任何明显的毒性。这两种化合物在SmartCube行为分析中进行了测试，并在每天给药（50 mg / kg，腹膜内）13天后显示出抗焦虑样的特征。综上所述，这些结果支持了以下假设：GSK-3β抑制可能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。

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