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CC BY 4.0 · Pharmaceutical Fronts 2022; 04(01): e9-e21
DOI: 10.1055/s-0042-1743415
Original Article

Synthesis and Biological Evaluation of a Series of Novel 1-(3-((6-Fluoropyridin-3-yl)oxy)propyl)piperazines as Dopamine/Serotonin Receptor Agonists

Xin-Li Du
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Yan-Na Ni
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
2   School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
,
Jiang-Rong Ji
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Ze-Hong Wan
3   Jiangsu Enhua Pharmaceutical Co., Ltd., Jiangsu, People's Republic of China
,
Zhi-Jing Hu
3   Jiangsu Enhua Pharmaceutical Co., Ltd., Jiangsu, People's Republic of China
,
Yu-Qiang Ge
3   Jiangsu Enhua Pharmaceutical Co., Ltd., Jiangsu, People's Republic of China
,
Jian-Qi Li
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Guan Wang
1   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
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Abstract

Evidence suggested that the use of partial dopamine D2/D3 receptor agonists may be a better choice for the treatment of Parkinson's disease (PD), and the stimulation of 5-HT1A receptors (mainly via nondopaminergic mechanisms) alleviates motor and nonmotor disorders of PD, implying that the multitarget approach may provide a double bonus for the treatment of the disease. In this study, 20 novel 1-(3-((6-fluoropyridin-3-yl)oxy)propyl)piperazine derivatives were designed and synthesized using a bioisosterism approach, and their activities for D2/D3/5-HT1A receptors were further tested. The results showed that several compounds exhibited a multitarget combination of D2/5-HT1A agonism. Compounds 7b and 34c showed agonistic activities on D2/D3/5-HT1A receptor. The EC50 value of 7b for D2/D3/5-HT1A receptor were 0.9/19/2.3 nmol/L, respectively; and the EC50 value of 34c for D2/D3/5-HT1A receptor were 3.3/10/1.4 nmol/L, respectively. In addition, 34c exhibited good metabolic stability (the half-life T 1/2 = 159.7 minutes) in vitro, which is of great significance for the further exploration of multitarget anti-PD drugs.

Keywords

Parkinson's disease - D2/D3 receptor partial agonist - 5-HT1A agonist

Ethics Statement

This article does not contain any studies with human participants or animals performed by any of the authors.




Publication History

Received: 22 November 2021

Accepted: 27 January 2022

Article published online:
31 March 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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