Exploring the Potential of Coumarin Derivatives on Serotonin Receptors 5-HT1A and 5HT2A

A series of 2- and 3-methoxyphenylpiperazine derivatives in combination with a 2-hydroxypropoxy linker and coumarins containing various substituents was synthesized and evaluated for antidepressant-like activity. Microwave-assisted synthesis was used, and the structures of all compounds were confirmed by ¹H, ¹³C NMR, and HRMS spectrometry. The affinity toward the 5-HT_1A and 5-HT_2A receptors was determined using radioligand binding assays and analyzed by molecular docking studies. Among the compounds evaluated, four demonstrated high affinity for the 5-HT_1A receptor with the following Ki values: 5-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2<i>H</i>-chromen-2-one (<b>5</b>) (90 nM), 6-acetyl-5-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propoxy)-4,7-dimethyl-2<i>H</i>-chromen-2-one (<b>7</b>) (90 nM), 7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl) propoxy)-4-methyl-2<i>H</i>-chromen-2-one (<b>10</b>) (87 nM), and 8-acetyl-7-(2-hydroxy-3-(4-(2-methoxy phenyl)piperazin-1-yl)propoxy)-4-methyl-2<i>H</i>-chromen-2-one (<b>11</b>) (96 nM), and four demonstrated high affinity for the 5-HT_2A receptor with the following Ki values: 6-acetyl-7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2<i>H</i>-chromen-2-one (<b>2</b>) (83 nM), 8-acetyl-7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-4-methyl-2<i>H</i>-chromen-2-one (<b>12</b>) (67 nM), 7-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl) propoxy)-2<i>H</i>-chromen-2-one (<b>13</b>) (18 nM), and 7-(2-hydroxy-3-(4-(3-methoxyphenyl)piperazin-1-yl)propoxy)-2<i>H</i>-chromen-2-one (<b>14</b>) (68 nM). In functional assays, 8-acetyl-7-(2-hydroxy-3-(4-(2-methoxyphenyl) piperazin-1-yl)propoxy)-4-methyl-2<i>H</i>-chromen-2-one (compound <b>11</b>) exhibited a significant 5-HT_1A antagonistic profile. Computational studies revealed the structural details responsible for the high affinity of selected derivatives, which were compared to known 5HT_1A partial agonists.