Antidepressant- and Anxiolytic-Like Effects of New Dual 5-HT₁A and 5-HT₇ Antagonists in Animal Models.

Karolina Pytka,Anna Rapacz,Barbara Mordyl,Barbara Filipek,Adam Gałuszka,Anna Waszkielewicz,Magdalena Jastrzębska-Więsek,Marian Błachuta,Anna Wesołowska,Henryk Marona,Jacek Sapa,Monika Głuch-Lutwin,Agata Siwek,Anna Partyka,Grzegorz Kazek,Adrian Olczyk

doi:10.1371/journal.pone.0142499

Karolina Pytka, Anna Rapacz + Show 14 more

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https://doi.org/10.1371/journal.pone.0142499

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Abstract

The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.

Highlights

Depression is a very serious mood disorder, characterized by low mood, anhedonia, reduced energy, and often comorbid with anxiety
HBK-14 showed a high affinity for adrenergic α1 receptors, a moderate affinity for serotonergic 5-HT2A and dopaminergic D2 receptors, and a very low affinity for Serotonin transporter (SERT)
HBK-15 showed a high affinity for adrenergic α1 and dopaminergic D2 receptors, a moderate affinity for serotonergic 5-HT2A and SERT, and no affinity for adrenergic α2 and β1 receptors (Table 1)

Summary

Introduction

Depression is a very serious mood disorder, characterized by low mood, anhedonia, reduced energy, and often comorbid with anxiety. 5-HT1A antagonists haven’t been introduced to the treatment of depression so far but they may have beneficial effects i.e. accelerating/enhancing the clinical effects of SSRIs [9]. A non-selective β-adrenoceptor and 5-HT1A receptor antagonist, enhanced the efficacy of SSRIs in depressed patients [10]; its effect on cardio-vascular system limits its clinical use. Another compound DU-125530—a potent pre- and postsynaptic 5-HT1A receptor antagonist—augmented SSRI-induced increases in extracellular 5-HT but did not accelerate the effects of fluoxetine in depressed individuals [11]. We should search for selective presynaptic 5-HT1A antagonists or multimodal compounds with weak 5-HT1A antagonistic properties

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