Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment
2023-10-13
发表期刊JOURNAL OF MEDICINAL CHEMISTRY
ISSN0022-2623
卷号66期号:20页码:14011–14028
发表状态已发表
DOI10.1021/acs.jmedchem.3c01034
摘要

The GPR139 receptor is an orphan G-protein-coupled receptor (GPCR) mainly found in the central nervous system and is a potential therapeutic target for the treatment of schizophrenia and drug addiction. Guided by the reported structure of GPR139, we conducted medicinal chemistry optimizations of TAK-041, the GPR139 agonist in clinical trials. New compounds with three different core structures were designed and synthesized, and their activity at GPR139 was evaluated. Among them, compounds 15a (EC50 = 31.4 nM) and 20a (EC50 = 24.7 nM) showed potent agonist activity at GPR139 and good pharmacokinetic properties. In murine schizophrenia models, both compounds rescued the social interaction deficits observed in BALB/c mice. Compound 20a also alleviated cognitive deficits in mice with a pharmacologically induced model of schizophrenia. These findings further demonstrated the potential of GPR139 agonists in alleviating the negative symptoms and cognitive deficits of schizophrenia. Compound 20a is worth further evaluation as an antischizophrenia drug candidate.

关键词Agonists Central nervous system Receptors Rodent models Schizophrenia
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收录类别SCI
语种英语
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文献类型期刊论文
条目标识符https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/346613
专题iHuman研究所_PI研究组_华甜组
iHuman研究所
iHuman研究所_公共科研平台_IT平台
iHuman研究所_PI研究组_程建军组
生命科学与技术学院_硕士生
生命科学与技术学院_博士生
iHuman研究所_PI研究组_周宁组
共同第一作者Tian Hua
通讯作者Ning Zhou; Jianjun Cheng
作者单位
1.iHuman Institute, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China
2.School of Life Science Technology, ShanghaiTech University, 393 Middle Huaxia Road, Shanghai 201210, China
第一作者单位iHuman研究所;  上海科技大学
通讯作者单位iHuman研究所;  上海科技大学
第一作者的第一单位iHuman研究所
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GB/T 7714
Jianhang Mao,Yilong Cui,Huan Wang,et al. Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment[J]. JOURNAL OF MEDICINAL CHEMISTRY,2023,66(20):14011–14028.
APA Jianhang Mao.,Yilong Cui.,Huan Wang.,Wenwen Duan.,Zhi-Jie Liu.,...&Jianjun Cheng.(2023).Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment.JOURNAL OF MEDICINAL CHEMISTRY,66(20),14011–14028.
MLA Jianhang Mao,et al."Design and Synthesis of Novel GPR139 Agonists with Therapeutic Effects in Mouse Models of Social Interaction and Cognitive Impairment".JOURNAL OF MEDICINAL CHEMISTRY 66.20(2023):14011–14028.
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