ABSTRACT
Trazodone, a well-known antidepressant drug widely used throughout the world, works as a 5-hydroxytryptamine (5-HT2) and α1-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-HT1A receptor ligands. Molecular modeling studies were performed to understand the differences in the activity toward 5-HT1A and 5-HT2A receptors between ligand 10a (2-(6-(4-(3-chlorophenyl)piperazin-1-yl)hexyl)-[1,2,4]triazolo[4,3-a]pyridin-3(2H)-one) (5-HT1A Ki = 16 nM) and trazodone. The docking results indicate the lack of the binding of ligand 10a to 5-HT2AR, which is consistent with the in vitro studies. On the other hand, the docking results for the 5-HT1A receptor indicate two possible binding modes. Crystallographic studies support the hypothesis of an extended conformation.
Subject(s)
Adrenergic Antagonists/chemistry , Antidepressive Agents/chemistry , Chemistry Techniques, Synthetic , Receptor, Serotonin, 5-HT1A/chemistry , Selective Serotonin Reuptake Inhibitors/chemistry , Trazodone/analogs & derivatives , Adrenergic Antagonists/chemical synthesis , Animals , Antidepressive Agents/chemical synthesis , Binding Sites , Carbonates/chemistry , Crystallography, X-Ray , Humans , Ligands , Microwaves , Molecular Docking Simulation , Potassium/chemistry , Protein Binding , Protein Conformation, alpha-Helical , Protein Conformation, beta-Strand , Protein Interaction Domains and Motifs , Receptor, Serotonin, 5-HT2A/chemistry , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Structural Homology, Protein , Structure-Activity Relationship , Time Factors , Trazodone/chemical synthesisABSTRACT
A rational design approach has been applied to synthesize a novel class of compounds with affinity for alpha(1) adrenergic receptors (AR). Molecular structures are characterized by a benzimidazolylpyridazinone or an imidazolylpyridazinone moiety, an original fragment in the field of the arylpiperazine compounds with alpha(1)-AR blocking properties. A 1.1 nM affinity toward alpha(1)-AR was found for compound 3, the most active of this series.
