Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H<sub>3</sub> Agents: Synthesis and Biological Evaluation
In this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound <b>11b</b> demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/N...
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MDPI AG
2024-11-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/29/22/5240 |
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| author | Quxiang Li Lili Ren Dongli Wang Junyong Luo Changda Xu Jian Feng Yufan Qiu Xiangqing Xu Guoguang Chen |
| author_facet | Quxiang Li Lili Ren Dongli Wang Junyong Luo Changda Xu Jian Feng Yufan Qiu Xiangqing Xu Guoguang Chen |
| author_sort | Quxiang Li |
| collection | DOAJ |
| description | In this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound <b>11b</b> demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/NET) and high affinity for histamine H<sub>3</sub> receptor (H<sub>3</sub>R), and displayed low affinity for off-target receptors (H1, α1) and hERG channels, which can reduce the prolongation of the QT interval. Molecular docking studies offered a rational binding model of compound <b>11b</b> when it forms a complex with SERT, NET, and the histamine H<sub>3</sub> receptor. In vivo behavioral studies, compound <b>11b</b> dose-dependently reduced the immobility duration in the mouse FST and TST assays without a stimulatory effect on the locomotor activity. Furthermore, compound <b>11b</b> had a favorable pharmacokinetic profile in rats. Thus, compound <b>11b</b> has the potential to develop a novel class of drugs for the treatment of depression. |
| format | Article |
| id | doaj-art-e05243740b4b40e2a730afc8ab2aab32 |
| institution | OA Journals |
| issn | 1420-3049 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-e05243740b4b40e2a730afc8ab2aab322025-08-20T02:04:55ZengMDPI AGMolecules1420-30492024-11-012922524010.3390/molecules29225240Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H<sub>3</sub> Agents: Synthesis and Biological EvaluationQuxiang Li0Lili Ren1Dongli Wang2Junyong Luo3Changda Xu4Jian Feng5Yufan Qiu6Xiangqing Xu7Guoguang Chen8School of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, ChinaSchool of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, ChinaJiangsu Key Laboratory of Central Nervous System Drug Research and Development, Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221116, ChinaSchool of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, ChinaJiangsu Key Laboratory of Central Nervous System Drug Research and Development, Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221116, ChinaJiangsu Key Laboratory of Central Nervous System Drug Research and Development, Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221116, ChinaPharmaron Beijing Co., Ltd., 6 Taihe Road, BDA, Beijing 100176, ChinaJiangsu Key Laboratory of Central Nervous System Drug Research and Development, Institute of Pharmaceutical Research, Jiangsu Nhwa Pharmaceutical Co., Ltd., Xuzhou 221116, ChinaSchool of Pharmacy, Nanjing Tech University, 30th South Puzhu Road, Nanjing 211816, ChinaIn this research, a variety of novel amphetamine derivatives were synthesized and assessed for their potential as multifaceted antidepressant agents. Among these compounds, compound <b>11b</b> demonstrated potent inhibitory effects on both serotonin and noradrenaline transporters (SERT/NET) and high affinity for histamine H<sub>3</sub> receptor (H<sub>3</sub>R), and displayed low affinity for off-target receptors (H1, α1) and hERG channels, which can reduce the prolongation of the QT interval. Molecular docking studies offered a rational binding model of compound <b>11b</b> when it forms a complex with SERT, NET, and the histamine H<sub>3</sub> receptor. In vivo behavioral studies, compound <b>11b</b> dose-dependently reduced the immobility duration in the mouse FST and TST assays without a stimulatory effect on the locomotor activity. Furthermore, compound <b>11b</b> had a favorable pharmacokinetic profile in rats. Thus, compound <b>11b</b> has the potential to develop a novel class of drugs for the treatment of depression.https://www.mdpi.com/1420-3049/29/22/5240amphetaminemultitargetantidepressantmolecular docking |
| spellingShingle | Quxiang Li Lili Ren Dongli Wang Junyong Luo Changda Xu Jian Feng Yufan Qiu Xiangqing Xu Guoguang Chen Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H<sub>3</sub> Agents: Synthesis and Biological Evaluation Molecules amphetamine multitarget antidepressant molecular docking |
| title | Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H<sub>3</sub> Agents: Synthesis and Biological Evaluation |
| title_full | Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H<sub>3</sub> Agents: Synthesis and Biological Evaluation |
| title_fullStr | Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H<sub>3</sub> Agents: Synthesis and Biological Evaluation |
| title_full_unstemmed | Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H<sub>3</sub> Agents: Synthesis and Biological Evaluation |
| title_short | Amphetamine Derivatives as Potent Central Nervous System Multitarget SERT/NET/H<sub>3</sub> Agents: Synthesis and Biological Evaluation |
| title_sort | amphetamine derivatives as potent central nervous system multitarget sert net h sub 3 sub agents synthesis and biological evaluation |
| topic | amphetamine multitarget antidepressant molecular docking |
| url | https://www.mdpi.com/1420-3049/29/22/5240 |
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