Molecular modeling aided design, synthesis, and activity evaluation of N-arylindole derivatives as GPR52 agonists

被引:0
作者
Wu, Qingkun [1 ,2 ]
Hou, Jingxuan [1 ]
Gu, Qingshan [1 ]
Shi, Meiqi [1 ]
Zheng, Lu [1 ,2 ]
机构
[1] Jiangsu Ocean Univ, Sch Pharm, Lianyungang 222000, Jiangsu, Peoples R China
[2] Jiangsu Inst Marine Resources Dev, Lianyungang 222005, Peoples R China
基金
中国国家自然科学基金;
关键词
GPR52; Agonists; Synthesis; Schizophrenia; Molecular docking; PHARMACOLOGICAL CHARACTERIZATION; SCHIZOPHRENIA; IDENTIFICATION; DISCOVERY; BURDEN; POTENT;
D O I
10.1016/j.molstruc.2024.140565
中图分类号
O64 [物理化学(理论化学)、化学物理学];
学科分类号
070304 ; 081704 ;
摘要
G protein-coupled receptor 52 (GPR52) is considered to be a promising target to improve the symptoms of psychiatric disorders and its agonists are expected to treat schizophrenia without traditional side effects. Several research institutions have reported some small molecule GPR52 agonists, which can be the starting point for rational drug development. In this study, a series of N-arylindole derivatives were designed and synthesized based on 3g according to classical pharmacochemical methods and computer aided drug design (CADD). The designed compounds exhibited good to excellent activities and the structure-activity relationship (SAR) study was explored. The results show that the connection mode between the hydrophilic head (Part I) and the indole ring (Part II) plays an important role in the GPR52 agonist activity. Among these compounds, compounds 16 and 21 have good GPR52 agonist activity (EC50 = 93 nM and 75 nM) and can inhibit hyperactive behavior in mice induced by MK-801 (EC50 =7.94 mg/kg and 6.64 mg/kg). These designed small molecules will provide new options for the development of novel GPR52 agonists.
引用
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页数:9
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