New 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives, with dual action at 5-HT1A serotonin receptors and serotonin transporter, as a new class of antidepressants

In a search toward new and efficient antidepressants, 1-aryl-3-(4-arylpiper azin-1-yl)propane derivatives were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT1A receptor antagonism. This dual pharmac ological profile should lead, in principle, to a rapid and pronounced enhan cement in serotoninergic neurotransmission and consequently to a more effic acious treatment of depression. The design was based on coupling structural moieties related to inhibition of serotonin reuptake, such as gamma -pheno xypropylamines, to arylpiperazines, typical 5-HT1A ligands. In binding stud ies, several compounds showed affinity at the 5-HT transporter and 5-HT1A r eceptors. Antidepressant-like activity was initially assayed in the forced swimming test with those compounds with K-i ( 200 nM in both binding studie s. Functional characterization was performed by measuring the intrinsic eff ect on rectal temperature in mice and also the antagonism to 8-OH-DPAT-indu ced hypothermia. The most efficacious compounds (12f, 23gE, 28a, and 28b) w ere further explored for their ability to antagonize 8-OH-DPAT-induced inhi bition of forskolin-stimulated cAMP formation in a cell line expressing the 5-HT1A receptor. Furthermore, the antidepressant-like properties of 12f, 2 8a, and 28b, which exhibited 5-HT1A receptor antagonistic property in the l atter study, were also evaluated in the learned helplessness test in rats. Among these three compounds, 28b (1-benzo[b]thiophene-3-yl)-3-[4-(2-methoxy phenyl)-1-ylpropan-1-ol) showed the higher affinity at both the 5-HT transp orter and 5-HT1A receptors (K-i = 20 nM in both cases) and was also active in the other pharmacological tests. Such a pharmacological profile could le ad to a new class of antidepressants with a dual mechanism of action and a faster onset of action.