We synthesized a series of aryl/heteroarylpiperazinyl derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin and evaluated their antidepressant-like activity. We used a fast, microwave-assisted synthesis protocol and 1H, 13C NMR and HRMS spectrometry to confirm the structure of all compounds. We also used radioligand binding assays to determine the affinities towards 5-HT1A and 5-HT2A receptors and performed molecular docking studies to rationalize obtained results. Among the evaluated compounds seven displayed high affinity to the 5-HT1A (3a-1.3 nM, 5a-1.6 nM, 10a-1.6 nM, 11a-1.0 nM, 3b-1.0 nM, 5b-0.8 nM and 11b-1.5 nM) as well as significant 5-HT1A antagonist profiles. The equilibrium dissociation constant values of tested compounds shown differential intrinsic activity (3a-190 nM, 3b-28 nM, 5a-48 nM, 5b-23 nM, 10b-180 nM, 11a-99 nM, 11b-38 nM) of antagonist mode. Molecular docking studies using a homology model of 5-HT1A revealed that ligand 5b is stabilized mainly by hydrogen bonds to Ser190.