6-Acetyl-5-hydroxy-4,7-dimethylcoumarin derivatives: Design, synthesis, modeling studies, 5-HT1A, 5-HT2A and D2 receptors affinity

Abstract

Molecular docking studies using appropriate 5-HT_1A, 5-HT_2A and D₂ 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, ¹H and ¹³C NMR. All newly prepared derivatives were evaluated for their 5-HT_1A, 5-HT_2A and D₂ receptor affinity. Seven of the synthesized derivatives showed very high affinities to 5-HT_1A 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_2A receptor (16-8.0 nM). In the case of the D₂ receptor none of the tested derivatives showed high affinity. Compounds 7 and 16 were identified as potent antagonists of the 5-HT_1A 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.

Keywords: 5-HT(1A), 5-HT(2A), D(2) receptor ligands; CNS activity; Hydroxycoumarin derivatives; Microwave-assisted synthesis; Molecular docking; TST tests.