Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors
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...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Georg Thieme Verlag KG
2021-12-01
|
| Series: | Pharmaceutical Fronts |
| Subjects: | |
| Online Access: | http://www.thieme-connect.de/DOI/DOI?10.1055/s-0041-1740049 |
| _version_ | 1798034760294989824 |
|---|---|
| author | Yan-Na Ni Xin-Li Du Tao Wang Yuan-Yuan Chen Xiang-Qing Xu Song Zhao Jian-Qi Li Guan Wang |
| author_facet | Yan-Na Ni Xin-Li Du Tao Wang Yuan-Yuan Chen Xiang-Qing Xu Song Zhao Jian-Qi Li Guan Wang |
| author_sort | Yan-Na Ni |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-11T20:48:48Z |
| format | Article |
| id | doaj.art-019f3efb5380418280792f7c4b417574 |
| institution | Directory Open Access Journal |
| issn | 2628-5088 2628-5096 |
| language | English |
| last_indexed | 2024-04-11T20:48:48Z |
| publishDate | 2021-12-01 |
| publisher | Georg Thieme Verlag KG |
| record_format | Article |
| series | Pharmaceutical Fronts |
| spelling | doaj.art-019f3efb5380418280792f7c4b4175742022-12-22T04:03:54ZengGeorg Thieme Verlag KGPharmaceutical Fronts2628-50882628-50962021-12-010304e183e19310.1055/s-0041-1740049Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 ReceptorsYan-Na Ni0Xin-Li Du1Tao Wang2Yuan-Yuan Chen3Xiang-Qing Xu4Song Zhao5Jian-Qi Li6Guan Wang7School of Chemistry and Chemical Engineering, Shanghai University of Engineering Science, Shanghai, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of ChinaJiangsu Enhua Pharmaceutical Co., Ltd., Jiangsu, People's Republic of ChinaJiangsu Enhua Pharmaceutical Co., Ltd., Jiangsu, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of ChinaNovel Technology Center of Pharmaceutical Chemistry, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of ChinaAbstract 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.http://www.thieme-connect.de/DOI/DOI?10.1055/s-0041-17400495-ht1a receptorsigma-1 receptorhigh affinityantidepressant |
| spellingShingle | Yan-Na Ni Xin-Li Du Tao Wang Yuan-Yuan Chen Xiang-Qing Xu Song Zhao Jian-Qi Li Guan Wang Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors Pharmaceutical Fronts 5-ht1a receptor sigma-1 receptor high affinity antidepressant |
| title | Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors |
| title_full | Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors |
| title_fullStr | Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors |
| title_full_unstemmed | Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors |
| title_short | Design, Synthesis, and Antidepressant Activity Study of Novel Aryl Piperazines Targeting Both 5-HT1A and Sigma-1 Receptors |
| title_sort | design synthesis and antidepressant activity study of novel aryl piperazines targeting both 5 ht1a and sigma 1 receptors |
| topic | 5-ht1a receptor sigma-1 receptor high affinity antidepressant |
| url | http://www.thieme-connect.de/DOI/DOI?10.1055/s-0041-1740049 |
| work_keys_str_mv | AT yannani designsynthesisandantidepressantactivitystudyofnovelarylpiperazinestargetingboth5ht1aandsigma1receptors AT xinlidu designsynthesisandantidepressantactivitystudyofnovelarylpiperazinestargetingboth5ht1aandsigma1receptors AT taowang designsynthesisandantidepressantactivitystudyofnovelarylpiperazinestargetingboth5ht1aandsigma1receptors AT yuanyuanchen designsynthesisandantidepressantactivitystudyofnovelarylpiperazinestargetingboth5ht1aandsigma1receptors AT xiangqingxu designsynthesisandantidepressantactivitystudyofnovelarylpiperazinestargetingboth5ht1aandsigma1receptors AT songzhao designsynthesisandantidepressantactivitystudyofnovelarylpiperazinestargetingboth5ht1aandsigma1receptors AT jianqili designsynthesisandantidepressantactivitystudyofnovelarylpiperazinestargetingboth5ht1aandsigma1receptors AT guanwang designsynthesisandantidepressantactivitystudyofnovelarylpiperazinestargetingboth5ht1aandsigma1receptors |