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
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 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 |
| DOI | 10.1111/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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