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

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...

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Bibliographic Details
Published in:Molecules (Basel, Switzerland) Switzerland), 2022-10, Vol.27 (21), p.7270
Main Authors: Zaręba, Przemysław, Partyka, Anna, Latacz, Gniewomir, Satała, Grzegorz, Zajdel, Paweł, Jaśkowska, Jolanta
Format: Article
Language:English
Subjects:
Affinity
Alcohol
Alkylation
antidepressant
Antidepressants
arylpiperazine
Biphenyl
Drug therapy
Ethanol
Hepatotoxicity
In vitro methods and tests
Kinases
Ligands
microwave
Pandemics
Proteins
Reducing agents
Reductive alkylation
Serotonin
Serotonin S1 receptors
Serotonin S7 receptors
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Summary: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.
ISSN:1420-3049
1420-3049
DOI:10.3390/molecules27217270