Abstract Background The previous study showed that arylpiperazine can condition affinity to α-adrenoceptors, 5-HT1A/5-HT2A receptors and compounds with arylpiperazine had antidepressant-like effect. The aim of this study was to determine the antidepressant-like activity of new arylpiperazines containing novel 8-alkoxy-purine-2,6-dione fragments. Methods New 3-chloroarylpiperazinylalkyl analogs of 8-alkoxy-purine-2,6-dione and their purine-2,6,8-trione analogs (2–5) were tested for their α1, α2, 5-HT1A,5-HT2A, and 5-HT7 receptor affinities in radioreceptor binding study. Moreover, in search for potential antidepressant properties of these compounds, the forced swim test in mice was conducted. Results Compounds 2 and 3 were potent 5-HT1A receptor ligands with Ki within the range on 12–15nM. All investigated compounds were found to be highly active 5-HT2A receptor (Ki 15–28nM) and α1 adrenoceptor (Ki 21–89nM) ligands. In the forced swim test all the compounds showed a significantly activity in spite of their reducing ability of locomotor activity. The most potent effect was produced by compound 4 and 5, which reduced the immobility time in this test in all used doses. Conclusion In our study the most potent antidepressant-like activity was produced by compounds 4 and 5, which are selective for the 5-HT2A and α1 receptors.