2. Academic Validation
  3. Design, synthesis, and biological profiling of novel aryl-spirocyclic diamine derivatives with potential antidepressant-like properties

Design, synthesis, and biological profiling of novel aryl-spirocyclic diamine derivatives with potential antidepressant-like properties

  • Eur J Med Chem. 2026 Jan 5:301:118198. doi: 10.1016/j.ejmech.2025.118198.
Jiefang Zheng 1,  Yaxin Tian 1,  Jiaxin Cheng 1,  Zhengtao Hu 2,  Junchi Zhang 1,  Feipu Yang 1,  Pengcheng Li 3,  Zhijuan Jiang 3,  Xudong Gong 3,  Qiongqiong Hou 3,  Guan Wang 3,  Vivien Shen 3,  Tianwen Hu 3,  Zhijian Xu 1,  Guanghui Tian 4,  Weiliang Zhu 5,  Yang He 6,  Jingshan Shen 1
Affiliations

Affiliations

  • 1 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.
  • 2 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China; School of Chinese Materia Medica, Nanjing University of Chinese Medicine, 210023, Nanjing, China.
  • 3 Vigonvita Shanghai Co., Ltd., Shanghai, 201210, China.
  • 4 Vigonvita Shanghai Co., Ltd., Shanghai, 201210, China. Electronic address: [email protected].
  • 5 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: [email protected].
  • 6 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: [email protected].
PMID: 41067053 DOI: 10.1016/j.ejmech.2025.118198
Abstract

To meet the clinical need for therapeutic efficacy against cognitive impairment and pain comorbidities in depression, a rational drug design approach was used in the current study to synthesize a series of spirocyclic diamine derivatives. Among them, (R)-D24 exhibited triple monoamine reuptake inhibitory activity (SERT, NET, and DAT), while D6 and D17 showed potent inhibitory activity against both SERT and 5-HT3AR. D6 and D17 have acceptable systemic exposure and oral bioavailability in mice and low clearance in human liver microsomes. D6 and D17 exhibited favorable safety profiles in hepatic, renal, and hERG toxicity assays and showed potent antidepressant-like effects in the forced swim test, supporting their potential for further preclinical investigation. In addition, the compound-target interactions of the key compounds were analyzed through molecular docking. These results highlight the rationality of our design and provide new perspectives for the development of antidepressant drugs.

Keywords

5-HT(3A)R antagonist; Antidepressants; Aryl-spirocyclic diamine derivatives; Multimodal monoaminergic compounds; Triple monoamine reuptake inhibitors.

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