中国科学院机构知识库网格
Chinese Academy of Sciences Institutional Repositories Grid
Identification of non-peptidic neuromedin U receptor modulators by a robust homogeneous screening assay

文献类型:期刊论文

作者Meng, Tao1; Su, Hao-ran1,2; Binkert, Christoph3; Fischli, Walter3; Zhou, Ling1,2; Shen, Jing-kang1; Wang, Ming-wei1,2
刊名ACTA PHARMACOLOGICA SINICA
出版日期2008-04
卷号29期号:4页码:517-527
关键词neuromedin U receptors modulators structure-activity relationship
ISSN号1671-4083
DOI10.1111/j.1745-7254.2008.00769.x
文献子类Article
英文摘要Aim: To develop a homogeneous binding assay for high-throughput screening (HTS) of hit compounds at human neuromedin U receptor (hNMU-R) 1 and to identify non-peptidic small molecule hNMU-R modulators through functional assessments and structure-activity relationship (SAR) analyses. Methods: Membrane preparations of Chinese hamster ovary cells (CHO-K1) stably expressing hNMU-R1, [I-125]hNMU-25, and wheat germ agglutinin-coupled microbeads were used to develop an HTS assay based on scintillation proximity assay (SPA) technology. This method was applied to a large-scale screening campaign against a diverse library of 36 000 synthetic compounds or natural products and subsequent confirmation studies. CHO-K1 cells stably expressing full-length hNMU-R1 or hNMU-R2 and a calcium-sensitive dye were employed to functionally measure intracellular calcium mobilization upon ligand stimulation. Preliminary SAR was determined based on limited structural modifications. Results: The K-i value (0.7 nmol/L) of hNMU-25 (the natural ligand) at hNMU-R1 measured by the SPA method was consistent with that reported in the literature, and the Z'factor for this HTS assay was 0.81. A total of 100 hits, showing more than 30% competitive inhibition on [I-125]hNMU-25 binding to hNMU-R1, were identified initially, 3 of which were confirmed thereafter to have reasonable hNMU-R1-binding affinities and similar chemical structures. Based on their common molecular skeleton, 203 analogs were synthesized and tested. Among the 16 analogs that retained variable hNMU-R1-binding abilities, 2 elicited calcium influx in both hNMU-R1 and hNMU-R2-ex-pressing cells, but none displayed antagonist activity. Conclusion: The homogeneous hNMU-R1 binding assay is an efficient and robust tool for screening potential hNMU-R modulators. Two non-selective hNMU-R agonists discovered are of low molecular weight nature with novel chemical structures. The preliminary SAR investigation suggests that both the triphenyl and guanidinol groups are crucial to the bioactivities observed.
WOS关键词PORCINE SPINAL-CORD ; CENTRAL-NERVOUS-SYSTEM ; CROP SMOOTH-MUSCLE ; CONTRACTILE ACTIVITY ; ENERGY HOMEOSTASIS ; PEPTIDES ; ANALOGS ; SUBTYPE ; LIGAND ; RAT
WOS研究方向Chemistry ; Pharmacology & Pharmacy
语种英语
CSCD记录号CSCD:3250462
WOS记录号WOS:000254559000017
出版者BLACKWELL PUBLISHING
源URL[http://119.78.100.183/handle/2S10ELR8/272945]  
专题药物化学研究室
中科院受体结构与功能重点实验室
新药研究国家重点实验室
国家新药筛选中心
通讯作者Wang, Ming-wei
作者单位1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China;
2.Natl Ctr Drug Screening, Shanghai 201203, Peoples R China;
3.Actelion Pharmaceut, CH-4123 Allschwil, Switzerland
推荐引用方式
GB/T 7714
Meng, Tao,Su, Hao-ran,Binkert, Christoph,et al. Identification of non-peptidic neuromedin U receptor modulators by a robust homogeneous screening assay[J]. ACTA PHARMACOLOGICA SINICA,2008,29(4):517-527.
APA Meng, Tao.,Su, Hao-ran.,Binkert, Christoph.,Fischli, Walter.,Zhou, Ling.,...&Wang, Ming-wei.(2008).Identification of non-peptidic neuromedin U receptor modulators by a robust homogeneous screening assay.ACTA PHARMACOLOGICA SINICA,29(4),517-527.
MLA Meng, Tao,et al."Identification of non-peptidic neuromedin U receptor modulators by a robust homogeneous screening assay".ACTA PHARMACOLOGICA SINICA 29.4(2008):517-527.

入库方式: OAI收割

来源:上海药物研究所

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