identificationofnonpeptidicneuromedinureceptormodulatorsbyarobusthomogeneousscreeningassay
文献类型：期刊论文
| 作者 | Tao MENG1 ; Haoran SU1; Christoph BINKERT2; Walter FISCHLI2; Ling ZHOU1; Jingkang SHEN1; Mingwei WANG1
|
| 刊名 | actapharmacologicasinica
 |
| 出版日期 | 2008 |
| 卷号 | 29期号:4页码:517 |
| 关键词 | PORCINE SPINAL-CORD CENTRAL-NERVOUS-SYSTEM CROP SMOOTH-MUSCLE CONTRACTILE ACTIVITY ENERGY HOMEOSTASIS PEPTIDES ANALOGS SUBTYPE LIGAND RAT |
| ISSN号 | 1671-4083 |
| 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, ~(125)IhNMU-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 Ki 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 ~(125)IhNMU-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. |
| 语种 | 英语 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/283518]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 1.中国科学院上海药物研究所 2.Actelion Pharmaceuticals |
| 推荐引用方式 GB/T 7714 | Tao MENG,Haoran SU,Christoph BINKERT,et al. identificationofnonpeptidicneuromedinureceptormodulatorsbyarobusthomogeneousscreeningassay[J]. actapharmacologicasinica,2008,29(4):517. |
| APA | Tao MENG.,Haoran SU.,Christoph BINKERT.,Walter FISCHLI.,Ling ZHOU.,...&Mingwei WANG.(2008).identificationofnonpeptidicneuromedinureceptormodulatorsbyarobusthomogeneousscreeningassay.actapharmacologicasinica,29(4),517. |
| MLA | Tao MENG,et al."identificationofnonpeptidicneuromedinureceptormodulatorsbyarobusthomogeneousscreeningassay".actapharmacologicasinica 29.4(2008):517. |
入库方式： OAI收割
来源：上海药物研究所
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