Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT(2A) and α1 receptor binding affinity

Article abstract of DOI:10.1021/jm970700n

A series of triazolopyridine derivatives (compounds 2a-1) were synthesized in order to explore the effect of modifications of the alkylpiperazine moiety of trazodone (fragment A) on binding affinity for 5HT(2A) and α₁ receptors. All of the synthesized compounds show a decrease of affinity for both 5HT(2A) and α₁ receptors, as compared to trazodone, with the exception of compounds 2b,c which bear a methyl group in an α position to the aliphatic nitrogen atom N₁. These compounds showed a decrease of affinity only for the α₁ receptor. The stereochemical influence of the piperazine moiety of compound 2c was also evaluated. Enantiomer (S)- 2c showed the most significant differences between 5HT(2A) and α₁ receptor affinity (IC₅₀ values) and among the corresponding functional properties (pA₂ values). Since (S)-2c cannot generate the metabolite 4-(3- chlorophenyl)piperazine this product was selected for further pharmacological studies.