Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic
文献类型：期刊论文
| 作者 | Huang, Huoming1; Wang, Wenli1; Xu, Xuejun2; Zhu, Chen1; Wang, Yujun2 ; Liu, Jinggen2; Li, Wei1; Fu, Wei1
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| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2020-03-01 |
| 卷号 | 189页码:14 |
| 关键词 | Selective MOR agonists Antinociception Analgesic Opioids Molecular mechanism |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2020.112070 |
| 通讯作者 | Liu, Jinggen() ; Li, Wei() ; Fu, Wei(wfu@fudan.edu.cn) |
| 英文摘要 | Management of moderate to severe pain by clinically used opioid analgesics is associated with a plethora of side effects. Despite many efforts have been dedicated to reduce undesirable side effects, moderate progress has been made. In this work, starting from Tramadol, a series of 3-((dimethylamino)methyl)-4hydroxy-4-(3-methoxyphenyl)piperidine-1-carboxamide derivatives were designed and synthesized, and their in vitro and in vivo activities were evaluated. Our campaign afforded selective opioid receptor (MOR) ligand 2a (K-i (MOR): 7.3 +/- 0.5 nM; K-iDOR: 849.4 +/- 96.6 nM; K-i KOR: 49.1 +/- 6.9 nM) as potent analgesic with ED50 of 3.1 mg/kg in 55 degrees C hot plate model. Its antinociception effect was blocked by opioid antagonist naloxone. High binding affinity toward MOR of compound 2a was associated with water bridge, salt bridge, hydrogen bond and hydrophobic interaction with MOR. The high selectivity of compound 2a for MOR over delta opioid receptor (DOR) and kappa opioid receptor (KOR) was due to steric hindrance of compound 2a with DOR and KOR. 2a, a compound with novel scaffold, could serve as a lead for the development of novel opioid ligands. (C) 2020 Elsevier Masson SAS. All rights reserved. |
| WOS关键词 | MU-OPIOID RECEPTOR ; G-PROTEIN ; MOLECULAR-MECHANISMS ; BIASED AGONISM ; TRV130 ; ANTAGONIST ; TOLERANCE ; TRAMADOL ; MORPHINE ; LIGANDS |
| 资助项目 | National Natural Science Foundation of China[81773635] ; Shanghai Science and Technology Development Funds[14431900500] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000518700000027 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/281177]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Liu, Jinggen; Li, Wei; Fu, Wei |
| 作者单位 | 1.Fudan Univ, Sch Pharm, Dept Med Chem, Shanghai 201203, Peoples R China 2.Chinese Acad Sci, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Huang, Huoming,Wang, Wenli,Xu, Xuejun,et al. Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2020,189:14. |
| APA | Huang, Huoming.,Wang, Wenli.,Xu, Xuejun.,Zhu, Chen.,Wang, Yujun.,...&Fu, Wei.(2020).Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,189,14. |
| MLA | Huang, Huoming,et al."Discovery of 3-((dimethylamino)methyl)-4-hydroxy-4-(3-methoxypheny1)-N-phenylpiperidine-1-carboxamide as novel potent analgesic".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 189(2020):14. |
入库方式： OAI收割
来源：上海药物研究所
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