Design, synthesis and biological evaluation of bivalent ligands against A(1)-D-1 receptor heteromers
文献类型：期刊论文
| 作者 | Shen, Jian; Zhang, Lei; Song, Wan-ling; Meng, Tao ; Wang, Xin; Chen, Lin; Feng, Lin-yin; Xu, Ye-chun; Shen, Jing-kang
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2013-03 |
| 卷号 | 34期号:3页码:441-452 |
| 关键词 | G protein-coupled receptors adenosine dopamine A(1) receptor D-1 receptor heterodimers bivalent ligands radiolabeled binding assay FRET molecular modeling |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2012.151 |
| 文献子类 | Article |
| 英文摘要 | Aim: To design and synthesize bivalent ligands for adenosine A(1)-dopamine D-1 receptor heteromers (A(1)-D1R), and evaluate their pharmacological activities. Methods: Bivalent ligands and their corresponding A(1)R monovalent ligands were designed and synthesized. The affinities of the bivalent ligands for A(1)R and D1R in rat brain membrane preparation were examined using radiolabeled binding assays. To demonstrate the formation of A(1)-D1R, fluorescence resonance energy transfer (FRET) was conducted in HEK293 cells transfected with D-1-CFP and A(1)-YFF. Molecular modeling was used to analyze the possible mode of protein-protein and protein-ligand interactions. Results: Two bivalent ligands for A(1)R and D1R (20a, 20b), as well as the corresponding A(1)R monovalent ligands (21a, 21b) were synthesized. In radiolabeled binding assays, the bivalent ligands showed affinities for A(1)R 10-100 times higher than those of the corresponding monovalent ligands. In FRET experiments, the bivalent ligands significantly increased the heterodimerization of A(1)R and D1R compared with the corresponding monovalent ligands. A heterodimer model with the interface of helixes 3, 4, 5 of A(1)R and helixes 1, 6, 7 from D1R was established with molecular modeling. The distance between the two ligand binding sites in the heterodimer model was approximately 48.4 angstrom, which was shorter than the length of the bivalent ligands. Conclusion: This study demonstrates the existence of A(1)-D1R in situ and a simultaneous interaction of bivalent ligands with both the receptors. |
| WOS关键词 | PROTEIN-COUPLED RECEPTOR ; ANGSTROM CRYSTAL-STRUCTURE ; DRUG DISCOVERY ; TRIPLET PUZZLE ; ADENOSINE A(1) ; D-1 ; ANTAGONIST ; PROBES ; PHARMACOLOGY ; HOMOLOGIES |
| 资助项目 | '100 Talents Project' of CAS[00000000] ; National ST Major Project[2012ZX09301-001-005] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:4768484 |
| WOS记录号 | WOS:000315931300015 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277715]  |
| 专题 | 药理学第二研究室 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 药物发现与设计中心 药物化学研究室 |
| 通讯作者 | Feng, Lin-yin |
| 作者单位 | Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Shen, Jian,Zhang, Lei,Song, Wan-ling,et al. Design, synthesis and biological evaluation of bivalent ligands against A(1)-D-1 receptor heteromers[J]. ACTA PHARMACOLOGICA SINICA,2013,34(3):441-452. |
| APA | Shen, Jian.,Zhang, Lei.,Song, Wan-ling.,Meng, Tao.,Wang, Xin.,...&Shen, Jing-kang.(2013).Design, synthesis and biological evaluation of bivalent ligands against A(1)-D-1 receptor heteromers.ACTA PHARMACOLOGICA SINICA,34(3),441-452. |
| MLA | Shen, Jian,et al."Design, synthesis and biological evaluation of bivalent ligands against A(1)-D-1 receptor heteromers".ACTA PHARMACOLOGICA SINICA 34.3(2013):441-452. |
入库方式： OAI收割
来源：上海药物研究所
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