7 beta-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues
文献类型：期刊论文
| 作者 | Sun, Hui-jiao4; Wang, Yu-hua1,2,5; Yuan, Cong-min4; Kong, Ling-hui4; Xu, Xue-jun2,5; Wang, Yu-jun2,5 ; Wu, Hai-hao4; Lin, Cheng4; Qian, Yuan-yuan4; Huang, Huo-ming4
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| 刊名 | BIOORGANIC & MEDICINAL CHEMISTRY
 |
| 出版日期 | 2018-08-07 |
| 卷号 | 26期号:14页码:4254-4263 |
| 关键词 | 7 beta-Methyl-nepenthone analogues KOR ligands Concept of hybridization Opioid receptor binding and functional activities |
| ISSN号 | 0968-0896 |
| DOI | 10.1016/j.bmc.2018.07.020 |
| 文献子类 | Article |
| 英文摘要 | With the purpose of identifying novel selective K opioid receptor (KOR) antagonists as potential antidepressants from nepenthone analogues, starting from N-nor-N-cyclopropylmethyl-nepenthone (SLL-020ACP), a highly selective and potent KOR agonist, a series of 7 beta-methyl-nepenthone analogues was conceived, synthesized and assayed on opioid receptors based on the concept of hybridization. According to the pharmacological results, the functional reversal observed in orvinol analogues by introduction of 7 beta-methyl substituent could not be reproduced in nepenthone analogues. Alternatively, introduction of 7 beta-methyl substituent was associated with substantial loss of both subtype selectivity and potency but not efficacy for nepenthone analogues, which was not found in 7 beta-methyl orvinol analogues. Surprisingly, SLL-603, a 7 beta-methyl analogue of SLL-020ACP, was identified to be a KOR full agonist. The possible molecular mechanism for the heterogeneity in activity cliff was also investigated. In conclusion, 7 beta-methyl substituent was a structural locus associated with activity cliff and demonstrated as a pharmacological heterogeneity between nepenthone and orvinol analogues that warrants further investigations. |
| WOS关键词 | KAPPA-OPIOID RECEPTOR ; ANTAGONIST ; ANTIDEPRESSANTS ; BUPRENORPHINE ; DEPRESSION ; DISORDERS ; POTENT ; DRUGS ; TRIAL ; ONSET |
| 资助项目 | CAS Key Laboratory of Receptor Research, Chinese Academy of Sciences, China[SIMM1706YKF-02] ; Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12040319] ; National Natural Foundation of China[81671322] ; National Natural Foundation of China[81773710] ; Youth Innovation Promotion Association of the Chinese Academy of Sciences[2017334] |
| WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
| 语种 | 英语 |
| WOS记录号 | WOS:000440942100043 |
| 出版者 | PERGAMON-ELSEVIER SCIENCE LTD |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/279624]  |
| 专题 | 药理学第二研究室 |
| 通讯作者 | Li, Wei; Liu, Jing-gen; Shao, Li-ming |
| 作者单位 | 1.Nanjing Univ Chinese Med, Sch Pharm, Nanjing 210046, Jiangsu, Peoples R China; 2.Chinese Acad Sci, Collaborat Innovat Ctr Brain Sci, Shanghai 201203, Peoples R China; 3.Fudan Univ, Minhang Hosp, 170 Xinsong Rd, Shanghai 201199, Peoples R China 4.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, Key Lab Receptor Res, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Sun, Hui-jiao,Wang, Yu-hua,Yuan, Cong-min,et al. 7 beta-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2018,26(14):4254-4263. |
| APA | Sun, Hui-jiao.,Wang, Yu-hua.,Yuan, Cong-min.,Kong, Ling-hui.,Xu, Xue-jun.,...&Shao, Li-ming.(2018).7 beta-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues.BIOORGANIC & MEDICINAL CHEMISTRY,26(14),4254-4263. |
| MLA | Sun, Hui-jiao,et al."7 beta-Methyl substituent is a structural locus associated with activity cliff for nepenthone analogues".BIOORGANIC & MEDICINAL CHEMISTRY 26.14(2018):4254-4263. |
入库方式： OAI收割
来源：上海药物研究所
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