Effect of modifications of the Alkylpiperazine moiety of trazodone on 5HT(2A) and alpha(1) receptor binding affinity

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