Evaluation of 1-Arylpiperazine Derivative of Hydroxybenzamides as 5-HT1A and 5-HT7 Serotonin Receptor Ligands: An Experimental and Molecular Modeling Approach

The synthesis and evaluation as 5-HT1A and 5-HT7 serotonin receptor ligands of the two sets of O-substituted hydroxybenzamides, structurally related to 2-{3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy}benzamide (1), (K-i 5-HT1A = 21 nM, 5-HT7 = 234 nM) are reported. To affect the affinity for 5-HT1A and 5-HT7 receptors, an amide moiety (2-6) and a hydrocarbon chain length (7-10) were modified. The serotonergic activity of compounds 2-10 was generally higher in the case of 5-HT1A receptors compared with 5-HT7 ones; the most active 5-HT1A ligands being mew-isomer 2 (K-i = 7 nM) and both analogs of 1 with the longest spacer, i.e., penta- and hexa-methylene derivatives 9 and 10 (K-i = 4 and 3 nM, respectively). The observed biological properties of compounds 1-10 were elucidated using molecular modeling procedures.