New, eco-friendly method for synthesis of 3-chlorophenyl and 1,1′-biphenyl piperazinylhexyl trazodone analogues with dual 5-HT1A/5-HT7 affinity and its antidepressant-like activity
Authors:
- Przemysław Zaręba,
- Anna Partyka,
- Gniewomir Latacz,
- Grzegorz Satała,
- Paweł Zajdel,
- Jolanta Jaśkowska
Abstract
Serotonin 5-HT1A and 5-HT7 receptors play an important role in the pathogenesis and pharmacotherapy of depression. Previously identified N-hexyl trazodone derivatives, 2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (7a·HCl), with high affinity for 5-HT1AR and 2-(6-(4-([1,1′-biphenyl]-2-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one hydrochloride (7b·HCl), a dual-acting 5-HT1A/5-HT7 receptor ligand, were prepared with a new microwave-assisted method. The protocol for the synthesis of 7a and 7b involved reductive alkylation under a mild reducing agent. We produced the final compounds with yield of 56–63% using ethanol or 51–56% in solvent-free conditions in 4 min. We then determined the 5-HT7R binding mode for compounds 7a and 7b using in silico methods and assessed the preliminary ADME and safety properties (hepatotoxicity and CYP3A4 inhibition) using in vitro methods for 7a·HCl and 7b·HCl. Furthermore, we evaluated antidepressant-like activity of the dual antagonist of 5-HT1A/5-HT7 receptors (7b·HCl) in the forced swim test (FST) in mice. The 5-HT1AR ligand (7a·HCl) with a much lower affinity for 5-HT7R compared to that of 7b·HCl was tested comparatively. Both compounds showed antidepressant activity, while 5-HT1A/5-HT7 double antagonist 7b·HCl showed a stronger and more specific response.
- Record ID
- CUT16f483d8ffd94072bf395683fb06f6b0
- Publication categories
- ;
- Author
- Journal series
- Molecules, ISSN , e-ISSN 1420-3049, Biweekly
- Issue year
- 2022
- Vol
- 27
- No
- 21
- Pages
- [1-15]
- Article number
- 7270
- Other elements of collation
- rys.; tab.; wykr.; Bibliografia (na s.) - 13-15; Bibliografia (liczba pozycji) - 42; Oznaczenie streszczenia - Abstr.; Numeracja w czasopiśmie - Vol. 27, Iss. 21
- Substantive notes
- This article belongs to the Special Issue: Current Approaches of Medicinal Chemistry in Neurological and Psychiatric Diseases
- Keywords in English
- microwave, reductive alkylation, antidepressant, serotonin, arylpiperazine
- ASJC Classification
- DOI
- DOI:10.3390/molecules27217270 Opening in a new tab
- URL
- https://www.mdpi.com/1420-3049/27/21/7270 Opening in a new tab
- Related project
- Synteza i ocena aktywności nowych ligandów działających na receptory ośrodkowego układu nerwowego (oun). . Project leader at PK: , ,
Projects financed by NCRD [Projekty finansowane przez NCBiR (NCBR (] - Language
- eng (en) English
- License
- Score (nominal)
- 140
- Score source
- journalList
- Score
- Publication indicators
- Additional fields
- Indeksowana w: Web of Science, Scopus
- Uniform Resource Identifier
- https://cris.pk.edu.pl/info/article/CUT16f483d8ffd94072bf395683fb06f6b0/
- URN
urn:pkr-prod:CUT16f483d8ffd94072bf395683fb06f6b0
* presented citation count is obtained through Internet information analysis, and it is close to the number calculated by the Publish or PerishOpening in a new tab system.