New, Eco-Friendly Method for Synthesis of 3-Chlorophenyl and 1,1′-Biphenyl Piperazinylhexyl Trazodone Analogues with Dual 5-HT(1A)/5-HT(7) Affinity and Its Antidepressant-like Activity

Serotonin 5-HT(1A) and 5-HT(7) 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-HT(1A)R 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-HT(1A)/5-HT(7) 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-HT(7)R 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-HT(1A)/5-HT(7) receptors (7b·HCl) in the forced swim test (FST) in mice. The 5-HT(1A)R ligand (7a·HCl) with a much lower affinity for 5-HT(7)R compared to that of 7b·HCl was tested comparatively. Both compounds showed antidepressant activity, while 5-HT(1A)/5-HT(7) double antagonist 7b·HCl showed a stronger and more specific response.