Structure-activity relationship analysis of meta-substituted N-cyclopropylmethyl-nornepenthones with mixed KOR/MOR activities
文献类型：期刊论文
| 作者 | Tang, Siyuan2,3; Hu, Shuyang1; Feng, Lijing7; Kong, Linghui3; Gui, Jiangwen6,7; Zhang, Ying2; Liu, Zi-han5; Zhang, Denggao3; Liu, An-An5; Liu, Xiao3 |
| 刊名 | EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
 |
| 出版日期 | 2025-05-05 |
| 卷号 | 289页码:15 |
| 关键词 | N-Cyclopropylmethyl-nornepenthones Structure-activity relationship MOR antagonist KOR agonist Substance use disorder |
| ISSN号 | 0223-5234 |
| DOI | 10.1016/j.ejmech.2025.117449 |
| 通讯作者 | Liu, Jinggen(jgliu@simm.ac.cn) ; Shao, Liming(limingshao@fudan.edu.cn) ; Wang, Yujun(yjwang@simm.ac.cn) ; Li, Wei(wei-li@fudan.edu.cn) |
| 英文摘要 | Substance Use Disorder (SUD) remains a significant global challenge, with current treatment options offering limited efficacy. Agonists targeting the kappa opioid receptor (KOR), especially those with additional mu opioid receptor (MOR) antagonistic activity, have shown promise in addressing SUD. In this study, a series of metasubstituted N-cyclopropylmethyl-nornepenthone derivatives were designed and synthesized, and their biological activities were assessed, leading to the identification of a KOR/MOR dual modulator, compound 10a. Unlike its para-positional isomer SLL-1062, where KOR activity is completely abolished, compound 10a displayed a singledigit nanomolar affinity for KOR, while its binding profiles for MOR and delta opioid receptor (DOR) were comparable to those of SLL-1062. Functional assays in vitro confirmed that compound 10a exhibited agonistic activity at KOR and antagonistic activity at MOR. The molecular basis for the introduction of a KOR component into compound 10a was further elucidated. Although compound 10a did not produce apparent antinociception in vivo, it effectively blocked morphine-induced antinociception and intestinal motility inhibition in rodent models. This study provides valuable insights into the development of MOR/KOR dual modulators and presents new lead compounds for potential treatments for SUD. |
| WOS关键词 | OPIOID RECEPTOR AGONIST ; KAPPA-AGONIST ; BETA-FUNALTREXAMINE ; PHARMACOLOGICAL CHARACTERIZATION ; MU-OPIOIDS ; ATPM-ET ; COCAINE ; POTENT ; MORPHINE ; ANTAGONIST |
| 资助项目 | Major Project of the Science and Technology Innovation 2030 of China (STI2030-Major Projects)[2021ZD0203500] ; Major Project of the Science and Technology Innovation 2030 of China (STI2030-Major Projects)[2021ZD0202900] ; Key R & D Program of Shandong Province, China[2024CXPT029] ; National Natural Science Foundation of China[82030112] ; Natural Science Foundation of Shanghai[24ZR1413700] ; Natural Science Foundation of Shanghai[23ZR1474900] ; Taishan Scholars Program and Shandong Laboratory Program[SYS202205] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:001444686400001 |
| 出版者 | ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/316653]  |
| 专题 | 中国科学院上海药物研究所 |
| 通讯作者 | Liu, Jinggen; Shao, Liming; Wang, Yujun; Li, Wei |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China 2.ShanghaiTech Univ, Sch Phys Sci & Technol, 393 Huaxiazhong Rd, Shanghai 201210, Peoples R China 3.Fudan Univ, Sch Pharm, Dept Med Chem, 826 Zhangheng Rd, Shanghai 201203, Peoples R China 4.Univ Chinese Acad Sci, 19 A Yuquan Rd, Beijing 100049, Peoples R China 5.Nanjing Univ Chinese Med, Sch Chinese Mat Med, Nanjing 210023, Peoples R China 6.Anhui Univ Chinese Med, Sch Pharm, Hefei 230012, Peoples R China 7.Bohai Rim Adv Res Inst Drug Discovery, Shandong Lab Yantai Drug Discovery, Yantai 264117, Shandong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Tang, Siyuan,Hu, Shuyang,Feng, Lijing,et al. Structure-activity relationship analysis of meta-substituted N-cyclopropylmethyl-nornepenthones with mixed KOR/MOR activities[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2025,289:15. |
| APA | Tang, Siyuan.,Hu, Shuyang.,Feng, Lijing.,Kong, Linghui.,Gui, Jiangwen.,...&Li, Wei.(2025).Structure-activity relationship analysis of meta-substituted N-cyclopropylmethyl-nornepenthones with mixed KOR/MOR activities.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,289,15. |
| MLA | Tang, Siyuan,et al."Structure-activity relationship analysis of meta-substituted N-cyclopropylmethyl-nornepenthones with mixed KOR/MOR activities".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 289(2025):15. |
入库方式： OAI收割
来源：上海药物研究所
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