Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics
Xiamuxi, H (Xiamuxi, Hainimu)1; Wang, Z (Wang, Zhen)1; Li, JF (Li, Jianfeng)1; Wang, Y (Wang, Yu)1; Wu, CH (Wu, Chunhui)1; Yang, FP (Yang, Feipu)1; Jiang, XR (Jiang, Xiangrui)1; Liu, YJ (Liu, Yongjian)1; Zhao, QJ (Zhao, Qingjie)1; Chen, WM (Chen, Weiming)[ 1 ]1; Zhang, J (Zhang, Jian)[ 4 ]1; Xie, YC (Xie, Yuanchao)1; Hud, TW (Hud, Tianwen)1; Xu, MS (Xu, Mingshuo)1; Guo, S (Guo, Shuang)1; Aisa, HA (Aisa, Haji Akber)1; He, Y (He, Yang)1; Shen, JS (Shen, Jingshan)1; Aisa, HA
2017
发表期刊BIOORGANIC & MEDICINAL CHEMISTRY
卷号25期号:17页码:4904-4916
摘要In the present study, a series of tetrahydropyridopyrimidinone derivatives, possessing potent dopamine D2, serotonin 5-HT1A and 5-HT2A receptors properties, was synthesized and evaluated as potential antipsychotics. Among them, 3-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)-9-hydroxy-2methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (10d) held the best pharmacological profile. It not only exhibited potent and balanced activities for D-2, 5-HT1A, and 5-HT2A receptors, but was also endowed with low activities for alpha(1A), 5-HT2C, H-1 receptors and hERG channels, suggesting a low propensity for inducing orthostatic hypotension, weight gain and QT prolongation. In animal models, compound 10d reduced phencyclidine-induced hyperactivity with a high threshold for catalepsy induction. On the basis of its robust in vitro potency and in vivo efficacy in preclinical models of schizophrenia, coupled with a good pharmacokinetic profile, 10d was selected as a candidate for further development.
关键词Dopamine Serotonin Multireceptor Atypical Antipsychotic 5-ht1a
DOI10.1016/j.bmc.2017.07.040
收录类别SCI
WOS记录号WOS:000407831300033
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文献类型期刊论文
条目标识符http://ir.xjipc.cas.cn/handle/365002/4992
专题省部共建新疆特有药用资源利用重点实验室
通讯作者Aisa, HA
作者单位1.Chinese Acad Sci, Xinjiang Tech Inst Phys & Chem, Urumqi 830011, Peoples R China
2.Univ Chinese Acad Sci, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Chinese Acad Sci, Shanghai Inst Mat Med, CAS Key Lab Receptor Res, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
4.Topharman Shanghai Co Ltd, 1088 Chuansha Rd, Shanghai 201209, Peoples R China
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Xiamuxi, H ,Wang, Z ,Li, JF ,et al. Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2017,25(17):4904-4916.
APA Xiamuxi, H .,Wang, Z .,Li, JF .,Wang, Y .,Wu, CH .,...&Aisa, HA.(2017).Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics.BIOORGANIC & MEDICINAL CHEMISTRY,25(17),4904-4916.
MLA Xiamuxi, H ,et al."Synthesis and biological investigation of tetrahydropyridopyrimidinone derivatives as potential multireceptor atypical antipsychotics".BIOORGANIC & MEDICINAL CHEMISTRY 25.17(2017):4904-4916.
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