Synthesis of a new series of aryl/heteroarylpiperazinyl derivatives of 8-acetyl-7-hydroxy-4-methylcoumarin with low nanomolar 5-HT1A affinities

Abstract 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 1 H, 13 C NMR and HRMS spectrometry to confirm the structure of all compounds. We also used radioligand binding assays to determine the affinities towards 5-HT 1A and 5-HT 2A receptors and performed molecular docking studies to rationalize obtained results. Among the evaluated compounds seven displayed high affinity to the 5-HT 1A ( 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-HT 1A 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-HT 1A revealed that ligand 5b is stabilized mainly by hydrogen bonds to Ser190.