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  3. Heterocycle-fused phenylcyclohexylamines as novel multi-target antagonists of N-methyl-D-aspartate (NMDA) receptor and monoamine transporter for treating depression

Heterocycle-fused phenylcyclohexylamines as novel multi-target antagonists of N-methyl-D-aspartate (NMDA) receptor and monoamine transporter for treating depression

  • Eur J Med Chem. 2025 Jul 5:291:117538. doi: 10.1016/j.ejmech.2025.117538.
Fuqiang Zheng 1,  Zhengtao Hu 2,  Hai Chen 3,  Jiaxin Cheng 4,  Qiongqiong Hou 5,  Jiefang Zheng 4,  Xudong Gong 5,  Jing Ji 6,  Nuriddinov Zayniddin 4,  Safomuddin Abduahadi 4,  Obul Mamateli 7,  Guan Wang 5,  Pengcheng Li 5,  Tianwen Hu 5,  Guanghui Tian 5,  Zhijian Xu 4,  Weiliang Zhu 4,  Haji Akber Aisa 8,  Jingshan Shen 9,  Yang He 10
Affiliations

Affiliations

  • 1 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Lingang Laboratory, Shanghai, 200031, China.
  • 2 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 3 School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 4 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 5 Vigonvita Shanghai Co., Ltd., Shanghai, 201210, China.
  • 6 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 7 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
  • 8 State Key Laboratory Basis of Xinjiang Indigenous Medicinal Plants Resource Utilization, Xinjiang Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Urumqi, 830011, China; University of Chinese Academy of Sciences, Beijing, 100049, China; School of Pharmacy, Xinjiang Medical University, Urumqi, 830054, China. Electronic address: haji@ms.xjb.ac.cn.
  • 9 School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing, 210023, China; State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: shenjingshan@simm.ac.cn.
  • 10 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; University of Chinese Academy of Sciences, Beijing, 100049, China. Electronic address: heyang@simm.ac.cn.
PMID: 40188584 DOI: 10.1016/j.ejmech.2025.117538
Abstract

Simultaneously modulating the glutamatergic and monoaminergic systems represents a promising strategy for treating depression. In this study, a series of multi-target antagonists targeting both NMDAR and monoamine transporters (SERT, DAT, and NET) was designed and evaluated for their antidepressant potential in vitro and in vivo. Among these heterocycle-fused phenylcyclohexylamine derivatives, compound A16 demonstrated potent and relatively balanced multi-target activity (A16: IC50(NMDAR): IC50(SERT): IC50(DAT): IC50(NET) = 1.8:1.0:1.9:1.3) compared to the lead compound S1. Pharmacokinetic studies revealed that A16 exhibited moderate clearance in microsomes and favorable oral brain exposure in mice. In vivo assessments showed that A16 and its R-isomer A17 exhibited significant antidepressant-like effects in the forced swim test and tail suspension test in mice. Notably, A17 demonstrated significant antidepressant-like effects at doses as low as 1 mg/kg, with no indication of addiction risk at 20 mg/kg. Collectively, these findings identify A17, a heterocycle-fused phenylcyclohexylamine as a promising scaffold for developing non-addictive, rapid-acting antidepressants.

Keywords

Antidepressants; Heterocycle-fused phenylcyclohexylamines; Monoamine transporter; Multi-target antagonists; NMDAR.

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