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Synthesis and biological evaluation of a series of multi-target N-substituted cyclic imide derivatives with potential antipsychotic effect
European Journal of Medicinal Chemistry ( IF 6.7 ) Pub Date : 2018-01-04 , DOI: 10.1016/j.ejmech.2017.12.099
Mingshuo Xu , Yu Wang , Feipu Yang , Chunhui Wu , Zhen Wang , Bin Ye , Xiangrui Jiang , Qingjie Zhao , Jianfeng Li , Yongjian Liu , Junchi Zhang , Guanghui Tian , Yang He , Jingshan Shen , Hualiang Jiang

In the present study, a series of multi-target N-substituted cyclic imide derivatives which possessed potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties were synthesized and evaluated as potential antipsychotics. Among these compounds, (3aR,4R,7S,7aS)-2-(4-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)butyl)-3a,4,7,7a-tetrahydro-1H-4,7-methanoisoindole-1,3(2H)-dione hydrochloride (3d) held a promising pharmacological profile. 3d not only showed potent and balanced in vitro activities on D2/5-HT1A/5-HT2A receptors, but also endowed with low to moderate activities on 5-HT2C, H1, α1A, M3 receptors and hERG channel, suggesting a low liability to induce side effects such as weight gain, orthostatic hypotension and QT prolongation. In animal behavioral studies, 3d reduced phencyclidine-induced hyperlocomotion with a high threshold for catalepsy induction. Compound 3d was selected as a potential antipsychotic candidate for further development.



中文翻译:

一系列具有潜在抗精神病作用的多目标N-取代环酰亚胺衍生物的合成和生物学评价

在本研究中,其具有强效的多巴胺d一系列多目标的N-取代环状酰亚胺衍生物的2,血清素5-HT 1A和5-HT 2A受体的性质,合成并评价潜在的抗精神病药物。在这些化合物中,(3aR,4R,7S,7aS)-2-(4-(4-(4-苯并[ b ]噻吩-4-基)哌嗪-1-基)丁基)-3a,4,7,7a-四氢-1H-4,7-甲基异吲哚-1,3(2H)-二酮盐酸盐(3d)具有良好的药理作用。3d不仅在D 2 / 5-HT 1A / 5-HT 2A上显示出强大而平衡的体外活性受体,但在5-HT 2C,H 1α1A,M 3受体和hERG通道上也具有低至中度的活性,提示引起副作用(如体重增加,体位性低血压和QT延长)的责任低。在动物行为研究中,3d降低了苯环利定诱发的运动过度,并导致僵直症的诱导阈值较高。化合物3d被选作潜在的抗精神病药物,可用于进一步开发。

更新日期:2018-01-04
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