Synthesis and Evaluation of Antidepressant‐like Activity of Some 4‐Substituted 1‐(2‐methoxyphenyl)Piperazine Derivatives

Abstract

A series of new derivatives of N-(2-methoxyphenyl)piperazine have been synthesized for their affinity toward serotonergic receptors and for their potential antidepressant-like activity. They have been evaluated toward receptors 5-HT1A , 5-HT6 , and 5-HT7 , as well as in vivo in the tail suspension, locomotor activity, and motor co-ordination tests. All the tested compounds proved very good affinities toward 5-HT1A and 5-HT7 receptors. The most promising compound was 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride, exhibiting affinity toward receptors Ki <1 nm (5-HT1A ) and Ki = 34 nm (5-HT7 ). Antidepressant-like activity (tail suspension test) was observed at 2.5 mg/kg b.w. (mice, i.p.), and the effect was stronger than that observed for imipramine (5 mg/kg b.w.). Sedative activity was observed at ED50 (locomotor test, mice, i.p.) = 17.5 mg/kg b.w. and neurotoxicity was observed at TD50 (rotarod, mice, i.p.) = 53.2 mg/kg b.w.

HBK-14 and HBK-15 with antidepressant-like and/or memory-enhancing properties increase serotonin levels in the hippocampus after chronic treatment in mice

“…HBK-14 and HBK-15 possessed significant antidepressant-like properties after acute treatment (Waszkielewicz et al 2015; Pytka et al 2015a). Both compounds showed α 1 -adrenolytic properties, and only HBK-15 did not lower blood pressure at antidepressant-like doses after single administration (Pytka et al 2016b).…”

“…1): 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15) were synthesized in the Department of Bioorganic Chemistry, Chair of Organic Chemistry, Pharmaceutical Faculty, Jagiellonian University (Waszkielewicz et al 2015). HBK-14, HBK-15, and scopolamine (Sigma, Germany) were dissolved in saline, and administered intraperitoneally (i.p.)…”

“…We previously reported significant antidepressant- and anxiolytic-like effects of two dual 5-HT 1A and 5-HT 7 receptor antagonists in various behavioral tests in rodents (Waszkielewicz et al 2015; Pytka et al 2015a). As a continuation of our previous experiments, in this study we aimed to investigate whether chronic administration of 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15) caused antidepressant-like effects and elevated serotonin levels in the murine hippocampus.…”

HBK-14 and HBK-15 Do Not Influence Blood Pressure, Lipid Profile, Glucose Level, or Liver Enzymes Activity after Chronic Treatment in Rats

“…The studied compounds (Fig 1): 1-[(2,6-dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) and 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-15) were synthesized in the Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University [10]. HBK-14, HBK-15, terazosin and thiopental (Rotexmedica, Germany) were dissolved in saline and administered intraperitoneally (i.p.).…”

Association of 5-HT1A Receptors with Affective Disorders

“…Several studies have suggested that the 5-HT 1A -Rs are potential targets for these psychiatric disorders [45][46][47][48][49]. In this regard, agonists (total and partial) to the 5-HT 1A -R have shown antidepressant and anxiolytic properties and have been employed as adjunct treatments to improve the therapeutic action of several antidepressant and anxiolytic drugs in several preclinical and clinical studies [50][51][52][53]. They offer a different pharmacological mechanism from that of the monoamine oxidase inhibitors (IMAO), tricyclic drugs, SSIRs, and other antidepressants.…”