Evaluation of 1‐arylpiperazine derivative of hydroxybenzamides as 5‐HT1A and 5‐HT7 serotonin receptor ligands: An experimental and molecular modeling approach

Abstract

AbstractThe 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), (Ki 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, 3, 4, 5, 6) and a hydrocarbon chain length (7, 8, 9, 10) were modified. The serotonergic activity of compounds 2, 3, 4, 5, 6, 7, 8, 9, 10 was generally higher in the case of 5‐HT1A receptors compared with 5‐HT7 ones; the most active 5‐HT1A ligands being meta‐isomer 2 (Ki = 7 nM) and both analogs of 1 with the longest spacer, i.e., penta‐ and hexa‐methylene derivatives 9 and 10 (Ki = 4 and 3 nM, respectively). The observed biological properties of compounds 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 were elucidated using molecular modeling procedures. J. Heterocyclic Chem., (2010).