2. Academic Validation
  3. Novel 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives as triple-target D2R/D3R/5-HT1AR agonists with robust antidepressant and antiparkinsonian activity

Novel 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives as triple-target D2R/D3R/5-HT1AR agonists with robust antidepressant and antiparkinsonian activity

  • Eur J Med Chem. 2026 Feb 5:303:118409. doi: 10.1016/j.ejmech.2025.118409.
Xinli Du 1,  Xuyan Liu 1,  Lei Li 2,  Zijin Feng 2,  Yisheng Zhong 1,  Kun Luo 1,  Zhijing Hu 3,  Peng Xie 4,  Guan Wang 5
Affiliations

Affiliations

  • 1 Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China; National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, 201203, China.
  • 2 Shanghai Shujing Biopharma Co., Ltd., Shanghai, China; Jiangsu Nhwa Pharmaceutical Co., Ltd. & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou, China.
  • 3 Shanghai Shujing Biopharma Co., Ltd., Shanghai, China; Jiangsu Nhwa Pharmaceutical Co., Ltd. & Jiangsu Key Laboratory of Central Nervous System Drug Research and Development, Xuzhou, China. Electronic address: huzhijing@nhwa-group.com.
  • 4 Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China; National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, 201203, China. Electronic address: xiepeng_sipi@126.com.
  • 5 Shanghai Institute of Pharmaceutical Industry Co., Ltd., China State Institute of Pharmaceutical Industry, Shanghai, 201203, China; National Key Laboratory of Lead Druggability Research, Shanghai Institute of Pharmaceutical Industry Co. Ltd., Shanghai, 201203, China. Electronic address: crown1357@sina.com.
PMID: 41338136 DOI: 10.1016/j.ejmech.2025.118409
Abstract

Parkinson's disease (PD) patients cause substantial motor impairment in daily life, with approximately 40 % patients also exhibiting comorbid depression. Current therapy predominantly employs dopamine D2R/D3R agonists, whereas 5-HT1AR activation confers clinically validated antidepressant benefits. Therefore, in this study, we report the discovery of compound 22b, a D2R/D3R/5-HT1AR muti-target agonist, which demonstrates both enhanced antiparkinsonian and antidepressant-like activities. A new series of 2,6-Diamino-4,5,6,7-tetrahydrobenzothiazole derivatives were designed, synthesized, and evaluated for receptor activity and hERG inhibition. Among them, compound 22b showed potent agonistic activity at D2R (EC50 = 1.29 nM), D3R (EC50 = 1.05 nM) and 5-HT1AR (EC50 = 153.50 nM), with favorable metabolic stability (T1/2p.o. = 3.77 h), neuroprotective effects and blood-brain barrier permeability (B/P = 0.348-0.506). In vivo, 22b significantly improved total distance traveled in MPTP-induced PD mouse models at 3 mg/kg (s.c.) and depressive-like behaviors in forced swim test in mice at low doses (1 mg/kg p.o.). These findings highlight 22b as a promising candidate for future exploration aiming at treatment of depression and Parkinson's disease.

Keywords

D(2)R/D(3)R/5-HT(1A)R muti-target agonist; Depression; Parkinson; Structural optimization.

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