Qingkun Wu , Jingxuan Hou , Qingshan Gu , Meiqi Shi , Lu Zheng
{"title":"分子建模辅助设计、合成和评估作为 GPR52 激动剂的 N-芳基吲哚衍生物的活性","authors":"Qingkun Wu , Jingxuan Hou , Qingshan Gu , Meiqi Shi , Lu Zheng","doi":"10.1016/j.molstruc.2024.140565","DOIUrl":null,"url":null,"abstract":"<div><div>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 <em>N</em>-arylindole derivatives were designed and synthesized based on <strong>3g</strong> 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 <strong>16</strong> and <strong>21</strong> have good GPR52 agonist activity (EC<sub>50</sub> = 93 nM and 75 nM) and can inhibit hyperactive behavior in mice induced by MK-801 (EC<sub>50</sub> =7.94 mg/kg and 6.64 mg/kg). These designed small molecules will provide new options for the development of novel GPR52 agonists.</div></div>","PeriodicalId":16414,"journal":{"name":"Journal of Molecular Structure","volume":null,"pages":null},"PeriodicalIF":4.0000,"publicationDate":"2024-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Molecular modeling aided design, synthesis, and activity evaluation of N-arylindole derivatives as GPR52 agonists\",\"authors\":\"Qingkun Wu , Jingxuan Hou , Qingshan Gu , Meiqi Shi , Lu Zheng\",\"doi\":\"10.1016/j.molstruc.2024.140565\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>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 <em>N</em>-arylindole derivatives were designed and synthesized based on <strong>3g</strong> 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 <strong>16</strong> and <strong>21</strong> have good GPR52 agonist activity (EC<sub>50</sub> = 93 nM and 75 nM) and can inhibit hyperactive behavior in mice induced by MK-801 (EC<sub>50</sub> =7.94 mg/kg and 6.64 mg/kg). These designed small molecules will provide new options for the development of novel GPR52 agonists.</div></div>\",\"PeriodicalId\":16414,\"journal\":{\"name\":\"Journal of Molecular Structure\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":4.0000,\"publicationDate\":\"2024-11-02\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Molecular Structure\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0022286024030734\",\"RegionNum\":2,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"CHEMISTRY, PHYSICAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Molecular Structure","FirstCategoryId":"92","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0022286024030734","RegionNum":2,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"CHEMISTRY, PHYSICAL","Score":null,"Total":0}
Molecular modeling aided design, synthesis, and activity evaluation of N-arylindole derivatives as GPR52 agonists
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.
期刊介绍:
The Journal of Molecular Structure is dedicated to the publication of full-length articles and review papers, providing important new structural information on all types of chemical species including:
• Stable and unstable molecules in all types of environments (vapour, molecular beam, liquid, solution, liquid crystal, solid state, matrix-isolated, surface-absorbed etc.)
• Chemical intermediates
• Molecules in excited states
• Biological molecules
• Polymers.
The methods used may include any combination of spectroscopic and non-spectroscopic techniques, for example:
• Infrared spectroscopy (mid, far, near)
• Raman spectroscopy and non-linear Raman methods (CARS, etc.)
• Electronic absorption spectroscopy
• Optical rotatory dispersion and circular dichroism
• Fluorescence and phosphorescence techniques
• Electron spectroscopies (PES, XPS), EXAFS, etc.
• Microwave spectroscopy
• Electron diffraction
• NMR and ESR spectroscopies
• Mössbauer spectroscopy
• X-ray crystallography
• Charge Density Analyses
• Computational Studies (supplementing experimental methods)
We encourage publications combining theoretical and experimental approaches. The structural insights gained by the studies should be correlated with the properties, activity and/ or reactivity of the molecule under investigation and the relevance of this molecule and its implications should be discussed.