Molecular docking studies using appropriate 5-HT, 5-HT and D receptors models were used to design sixteen new 5-hydroxycoumarin derivatives with piperazine moiety (3–18). The microwave radiation have been used to synthesize them and their structures have been confirmed using mass spectrometry, H and C NMR. All newly prepared derivatives were evaluated for their 5-HT, 5-HT and D receptor affinity. Seven of the synthesized derivatives showed very high affinities to 5-HT receptor (3–4.0 nM, 6–4.0 nM, 7–1.0 nM, 9–6.0 nM, 15–4.3 nM, 16–1.0 nM, 18–3.0 nM) and one of them showed high affinities to 5-HT receptor (16–8.0 nM). In the case of the D receptor none of the tested derivatives showed high affinity. Compounds 7 and 16 were identified as potent antagonists of the 5-HT receptor as shown by the [35S]GTPcS binding assay but they didn’t show any antidepressant effect at the single dose tested (10 mg/kg) in the tail suspension tests.