| Summary: | Trazodone, a well-known antidepressant drug widely used throughout the world, works as a 5-hydroxytryptamine (5-HT<sub>2</sub>) and α<sub>1</sub>-adrenergic receptor antagonist and a serotonin reuptake inhibitor. Our research aimed to develop a new method for the synthesis of trazodone and its derivatives. In the known methods of the synthesis of trazodone and its derivatives, organic and toxic solvents are used, and the synthesis time varies from several to several dozen hours. Our research shows that trazodone and its derivatives can be successfully obtained in the presence of potassium carbonate as a reaction medium in the microwave field in a few minutes. As a result of the research work, 17 derivatives of trazodone were obtained, including compounds that exhibit the characteristics of 5-HT<sub>1A</sub> receptor ligands. Molecular modeling studies were performed to understand the differences in the activity toward 5-HT<sub>1A</sub> and 5-HT<sub>2A</sub> receptors between ligand <b>10a</b> (2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2<i>H</i>)-one) (5-HT<sub>1A</sub> <i>K</i><sub>i</sub> = 16 nM) and trazodone. The docking results indicate the lack of the binding of ligand <b>10a</b> to 5-HT<sub>2A</sub>R, which is consistent with the in vitro studies. On the other hand, the docking results for the 5-HT<sub>1A</sub> receptor indicate two possible binding modes. Crystallographic studies support the hypothesis of an extended conformation.
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