Effect of modifications of the alkylpiperazine moiety of trazodone on 5HT2A and α1 receptor binding affinity

A series of triazolopyridine derivatives (compounds 2a−l) were synthesized in order to explore the effect of modifications of the alkylpiperazine moiety of trazodone (fragment A) on binding affinity for 5HT2A and α1 receptors. All of the synthesized compounds show a decrease of affinity for both 5HT2A 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 5HT2A 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.