New 1-Aryl-3-(4-arylpiperazin-1-yl)propane Derivatives, with Dual Action at 5-HT_1A Serotonin Receptors and Serotonin Transporter, as a New Class of Antidepressants

Abstract

In a search toward new and efficient antidepressants, 1-aryl-3-(4-arylpiperazin-1-yl)propane derivatives were designed, synthesized, and evaluated for 5-HT reuptake inhibition and 5-HT1A receptor antagonism. This dual pharmacological profile should lead, in principle, to a rapid and pronounced enhancement in serotoninergic neurotransmission and consequently to a more efficacious treatment of depression. The design was based on coupling structural moieties related to inhibition of serotonin reuptake, such as gamma-phenoxypropylamines, to arylpiperazines, typical 5-HT1A ligands. In binding studies, several compounds showed affinity at the 5-HT transporter and 5-HT1A receptors. Antidepressant-like activity was initially assayed in the forced swimming test with those compounds with Ki < 200 nM in both binding studies. Functional characterization was performed by measuring the intrinsic effect on rectal temperature in mice and also the antagonism to 8-OH-DPAT-induced hypothermia. The most efficacious compounds (12f, 23gE, 28a, and 28b) were further explored for their ability to antagonize 8-OH-DPAT-induced inhibition of forskolin-stimulated cAMP formation in a cell line expressing the 5-HT1A receptor. Furthermore, the antidepressant-like properties of 12f, 28a, and 28b, which exhibited 5-HT1A receptor antagonistic property in the latter 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-methoxyphenyl)-1-ylpropan-1-ol) showed the higher affinity at both the 5-HT transporter and 5-HT1A receptors (Ki = 20 nM in both cases) and was also active in the other pharmacological tests. Such a pharmacological profile could lead to a new class of antidepressants with a dual mechanism of action and a faster onset of action.

Modulation of Serotonergic Function in Rat Brain by VN2222, a Serotonin Reuptake Inhibitor and 5-HT1A Receptor Agonist

“…The affinity of VN2222 for 5-HT 1A receptors is lower than that of 8-OH-DPAT (Martínez-Esparza et al, 2001). In agreement, the calculated ED 50 of VN2222 to suppress 5-HT cell firing (15 mg/kg i.v.)…”

“…At the same time, they could enhance serotonergic transmission through the activation of postsynaptic 5-HT 1A receptors and, unlike selective 5-HT 1A receptor agonists, they could keep the tone on other postsynaptic 5-HT receptors because of their ability to inhibit 5-HT reuptake. The present study reports on the in vivo effects of one such compound (VN2222; Figure 1) (Martínez-Esparza et al, 2001) on the serotonergic system in rat brain using microdialysis and single-unit extracellular recordings.…”

An Active Search Method for Finding Objects with Near-Optimal Property Values within a Given Set

“…The biological property corresponds to experimental values of 5-HT 1A receptor affinity stated in terms of the inhibition constant K i , as reported in. 10 In the present study, this property is expressed as pK i = -log K i , with values ranging from 5.3 to 8.3.…”

“…The first case study concerns a quantitative structureactivity relationships (QSAR) investigation involving a set of antidepressant compounds (arylpiperazine) with inhibition constants (K i ) measured elsewhere. 10 In this type of problem, the x-values correspond to molecular descriptors of the compounds under consideration, which are derived through theoretical calculations by using a suitable software. In contrast, the y-property is obtained by experimental procedures such as in vitro or in vivo studies.…”

Trends in the Development of New Antidepressants. Is there a Light at the End of the Tunnel?

“…Further support of this hypothesis was the observation that a 5-HT 1A antagonist WAY 100635 was found to potentiate the antidepressant effects of several SSRIs [79,80]. Consequently, there has been considerable interest by several groups to identify drug design strategies focusing on incorporating a 5-HT 1A antagonist component into a 5-HT reuptake inhibitor to bring about a more immediate and complete antidepressant effect [81][82][83][84][85]. Perez et al [81] synthesized several molecules by covalent coupling of known 5-HT 1A antagonists of the aminopropanol family (pindolol, propranolol and penbutolol) with SSRIs like fluoxetine or paroxetine and with the new serotonin noradrenalin reuptake inhibitor antidepressant milnacipram (Fig.…”