Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel mu opioid receptor ligands
文献类型：期刊论文
| 作者 | Shen, Qing1; Qian, Yuan-yuan1; Xu, Xue-jun2; Li, Wei1; Liu, Jing-gen2 ; Fu, Wei1
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| 刊名 | ACTA PHARMACOLOGICA SINICA
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| 出版日期 | 2015-07 |
| 卷号 | 36期号:7页码:887-894 |
| 关键词 | mu-opioid receptor tramadol morphine molecular docking |
| ISSN号 | 1671-4083 |
| DOI | 10.1038/aps.2014.171 |
| 文献子类 | Article |
| 英文摘要 | Aim: Tramadol is an atypical opioid analgesic with low potential for tolerance and addiction. However, its opioid activity is much lower than classic opiates such as morphine. To develop novel analgesic and further explore the structure activity relationship (SAR) of tramadol skeleton. Methods: Based on a three-dimensional (3D) structure superimposition and molecular docking study, we found that M1 (the active metabolite of tramadol) and morphine have common pharmacophore features and similar binding modes at the mu opioid receptor in which the substituents on the nitrogen atom of both compounds faced a common hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. In this study, N-phenethylnormorphine was docked to the mu opioid receptor. It was found that the N-substituted group of N-phenethylnormorphine extended into a hydrophobic pocket formed by Trp2936.48 and Tyr3267.43. This hydrophobic interaction may contribute to the improvement of its opioid activities as compared with morphine. The binding modes of M1, morphine and N-phenethylnormorphine overlapped, indicating that the substituent on the nitrogen atoms of the three compounds may adopt common orientations. A series of N-phenylalkyl derivatives from the tramadol scaffold were designed, synthesized and assayed in order to generate a new type of analgesics. Results: As a result, compound 5b was identified to be an active candidate from these compounds. Furthermore, the binding modes of 5b and morphine derivatives in the mu opioid receptor were comparatively studied. Conclusion: Unlike morphine-derived structures in which bulky N-substitution is associated with improved opioid-like activities, there seems to be a different story for tramadol, suggesting the potential difference of SAR between these compounds. A new type of interaction mechanism in tramadol analogue (5b) was discovered, which will help advance potent tramadol-based analgesic design. |
| WOS关键词 | POSTHERPETIC NEURALGIA ; PREMATURE EJACULATION ; DIABETIC-NEUROPATHY ; DOUBLE-BLIND ; PAIN ; EFFICACY ; RELEASE ; TRIAL |
| 资助项目 | Science and Technology Commission of Shanghai Municipality[14431990500] ; National Natural Science Foundation of China[81473136] ; National Natural Science Foundation of China[30901857] |
| WOS研究方向 | Chemistry ; Pharmacology & Pharmacy |
| 语种 | 英语 |
| CSCD记录号 | CSCD:5474160 |
| WOS记录号 | WOS:000357477600014 |
| 出版者 | ACTA PHARMACOLOGICA SINICA |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276481]  |
| 专题 | 药理学第二研究室 |
| 通讯作者 | Li, 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 | Shen, Qing,Qian, Yuan-yuan,Xu, Xue-jun,et al. Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel mu opioid receptor ligands[J]. ACTA PHARMACOLOGICA SINICA,2015,36(7):887-894. |
| APA | Shen, Qing,Qian, Yuan-yuan,Xu, Xue-jun,Li, Wei,Liu, Jing-gen,&Fu, Wei.(2015).Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel mu opioid receptor ligands.ACTA PHARMACOLOGICA SINICA,36(7),887-894. |
| MLA | Shen, Qing,et al."Design, synthesis and biological evaluation of N-phenylalkyl-substituted tramadol derivatives as novel mu opioid receptor ligands".ACTA PHARMACOLOGICA SINICA 36.7(2015):887-894. |
入库方式： OAI收割
来源：上海药物研究所
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