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Serotonin 5-HT_1A and 5-HT₇ receptors play an important role in the pathogenesis and pharmacotherapy of depression. Previously identified <i>N</i>-hexyl trazodone derivatives, 2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-<i>a</i>]pyridin-3(2<i>H</i>)-one hydrochloride (<b>7a·HCl</b>), with high affinity for 5-HT_1AR and 2-(6-(4-([1,1′-biphenyl]-2-yl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-<i>a</i>]pyridin-3(2<i>H</i>)-one hydrochloride (<b>7b·HCl</b>), a dual-acting 5-HT_1A/5-HT₇ receptor ligand, were prepared with a new microwave-assisted method. The protocol for the synthesis of <b>7a</b> and <b>7b</b> 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 <b>7a</b> and <b>7b</b> using in silico methods and assessed the preliminary ADME and safety properties (hepatotoxicity and CYP3A4 inhibition) using in vitro methods for <b>7a·HCl</b> and <b>7b·HCl</b>. Furthermore, we evaluated antidepressant-like activity of the dual antagonist of 5-HT_1A/5-HT₇ receptors (<b>7b·HCl</b>) in the forced swim test (FST) in mice. The 5-HT_1AR ligand (<b>7a·HCl</b>) with a much lower affinity for 5-HT₇R compared to that of <b>7b·HCl</b> was tested comparatively. Both compounds showed antidepressant activity, while 5-HT_1A/5-HT₇ double antagonist <b>7b·HCl</b> showed a stronger and more specific response.