New, Eco-Friendly Method for Synthesis of 3-Chlorophenyl and 1,1'-Biphenyl Piperazinylhexyl Trazodone Analogues with Dual 5-HT/5-HT Affinity and Its Antidepressant-like Activity.

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