CC BY 4.0 · Pharmaceutical Fronts 2021; 03(04): e183-e193
DOI: 10.1055/s-0041-1740049
Original Article

Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors

Yan-Na Ni
1   School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of China
2   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Xin-Li Du
2   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Tao Wang
2   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Yuan-Yuan Chen
2   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Xiang-Qing Xu
3   Jiangsu Enhua Pharmaceutical Co., Ltd., Jiangsu, People's Republic of China
,
Song Zhao
3   Jiangsu Enhua Pharmaceutical Co., Ltd., Jiangsu, People's Republic of China
,
Jian-Qi Li
2   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
2   Novel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
› Author Affiliations


Abstract

A total of 20 novel aryl piperazine derivatives were designed and synthesized, and their structures were confirmed by mass spectrometry and nuclear magnetic resonance analyses. Their 5-HT1A and sigma-1 receptor affinities were determined, and six of them showed high affinities (K i < 20 nmol/L) to both 5-HT1A and sigma-1 targets. Then, metabolic stability (T 1/2) tests of six compounds in rat and human liver microsomes were performed. Our data indicated that compound 27 has both high affinity for 5-HT1A and sigma-1 receptors (5-HT1A: K i = 0.44 nmol/L; sigma-1: K i = 0.27 nmol/L), and good metabolic stability (T 1/2 values are 21.7 and 24.6 minutes, respectively). Interestingly, results from the forced swimming test, mouse tail suspension test, and preliminary pharmacokinetic test suggested the marked antidepressant activity, good pharmacokinetic characteristics, and low toxicity of compound 27 in the two models. In conclusion, compound 27 has great value of further study as an active molecule of antidepressant drugs.

Ethics Statement

The present study was approved by the animal ethics committee and abides by the relevant agreements of the Jiangsu Enhua Pharmaceutical Co., Ltd., Jiangsu, People's Republic of China.




Publication History

Received: 03 September 2021

Accepted: 09 October 2021

Article published online:
25 December 2021

© 2021. 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