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

Pytka, Karolina; Głuch‐Lutwin, Monika; Knutelska, Joanna; Jakubczyk, Magdalena; Kotańska, Magdalena

doi:10.1371/journal.pone.0165495

Cited by 8 publications

(5 citation statements)

References 35 publications

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“…Interestingly, HBK-15 showed no significant affinity for histamine or muscarinic receptors, which agrees with our previous biofunctional studies [41,42]. Affinity for histamine or muscarinic receptors is an undesirable feature of central-acting compounds, as interaction with these receptors may cause side effects such as weight gain, sedation, tachycardia, blurred vision, and others [43,44].…”

Section: Discussionsupporting

confidence: 85%

HBK-15, a Multimodal Compound, Showed an Anxiolytic-Like Effect in Rats

et al. 2022

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Anxiety is a common mental disorder, and its prevalence has lately increased because of the COVID-19 pandemic. Unfortunately, the available anxiolytics are often ineffective, and most possess addictive potential. Thus, searching for novel compounds is essential. In our previous studies, we selected a multimodal compound, HBK-15, which showed a fast antidepressant-like effect in animal models of depression. HBK-15 demonstrated a high affinity for serotonin 5-HT1A receptors and moderate for 5-HT7, dopamine D2, and α1-adrenoceptors. Based on the receptor profile and preliminary studies, we aimed to investigate the anxiolytic potential of HBK-15 using the conditioned-response rat model of anxiety, i.e., the Vogel drinking test. We performed hot plate and free-drinking tests to exclude false positive results in the Vogel test. Using radioligand binding studies, we also investigated the affinity of the compound for the selected biological targets, which play a role in anxiety. Our experiments revealed that HBK-15 showed an anxiolytic-like effect in rats (5 mg/kg) without influencing the pain threshold or the amount of water consumed in the free-drinking test. Furthermore, the tested compound did not show a significant affinity for the selected biological targets, which suggests that its anxiolytic-like mechanism of action could be connected with the interaction with other receptors. This study indicates that multimodal compounds with a receptor profile similar to HBK-15 could be an attractive therapeutic option for patients with a generalized anxiety disorder. However, more studies are required to determine the exact mechanism of action of HBK-15 and its safety profile.

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Section: Discussionsupporting

confidence: 85%

HBK-15, a Multimodal Compound, Showed an Anxiolytic-Like Effect in Rats

et al. 2022

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“…Although the compound moderately antagonized D 2 (IC 50 = 68 nM) and very weakly 5-HT 2A receptors (IC 50 = 4459 nM), it did not show antipsychotic-like or cataleptogenic properties (unpublished results). HBK-14 and HBK-15 presented negligible cholinolytic [ 22 ] and antihistaminic activities [ 23 ]. We proved that despite α 1 -adrenolytic properties [ 24 ], neither HBK-14 nor HBK-15 lowered blood pressure at antidepressant- and anxiolytic-like doses after chronic treatment [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

“…HBK-14 and HBK-15 presented negligible cholinolytic [ 22 ] and antihistaminic activities [ 23 ]. We proved that despite α 1 -adrenolytic properties [ 24 ], neither HBK-14 nor HBK-15 lowered blood pressure at antidepressant- and anxiolytic-like doses after chronic treatment [ 23 ]. HBK-15 did not exhibit hypotensive activity even after single administration [ 24 ].…”

Section: Introductionmentioning

confidence: 99%

“…HBK-15 did not exhibit hypotensive activity even after single administration [ 24 ]. Interestingly, unlike most antidepressants, the compound showed memory-enhancing properties and ameliorated memory deficits induced by scopolamine in mice [ 23 ]. Both compounds administered chronically increased serotonin levels in murine hippocampus [ 22 ].…”

Section: Introductionmentioning

confidence: 99%

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Single Administration of HBK-15—a Triple 5-HT1A, 5-HT7, and 5-HT3 Receptor Antagonist—Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone

et al. 2017

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Studies suggest that the blockade of 5-HT1A, 5-HT7, and 5-HT3 receptor may increase the speed of antidepressant response. 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), dual 5-HT1A and 5-HT7 antagonists, showed significant antidepressant- and anxiolytic-like properties in our previous tests in rodents. In this study, we aimed to investigate their antidepressant potential using mouse model of corticosterone-induced depression. We chose sucrose preference test, forced swim test, and elevated plus maze to determine anhedonic-, antidepressant-, and anxiolytic-like activities. We also evaluated the influence of the active compound on brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) levels in the hippocampus. Moreover, for both compounds, we performed biofunctional (5-HT3 receptor) and pharmacokinetic studies. We found that HBK-14 and HBK-15 were potent 5-HT3 receptor antagonists. HBK-14 (2.5 mg/kg) and HBK-15 (1.25 mg/kg) after intravenous (i.v.) and intraperitoneal (i.p.) administration permeated the blood–brain barrier with brain/plasma ratio lower than 1. The bioavailability of studied compounds after i.p. administration was 15% for HBK-14 and 54% for HBK-15. Chronic administration of HBK-15 (1.25 mg/kg) and fluoxetine (10 mg/kg) protected corticosterone-treated mice from anhedonic-, depressive-, and anxiety-like behaviors, as well as decreases in BDNF and NGF levels in the hippocampus. HBK-14 (2.5 mg/kg) counteracted anxiety-like behaviors in corticosterone-treated mice. Single administration of HBK-15 (1.25 mg/kg) and ketamine (1 mg/kg) reversed depression-like behavior and regulated decreased BDNF level in the hippocampus in corticosterone-treated mice. Our results suggest that simultaneous blockade of serotonergic 5-HT1A, 5-HT7, and 5-HT3 receptors might accelerate antidepressant response.

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“…Interestingly, the pharmacological profile of HBK-10 in the above behavioral tests resembles the profile of HBK-15, a compound showing a rapid antidepressant-like effect in rodent models of depression, as well as additional pharmacological properties, such as anxiolytic-like or procognitive effects [ 18 , 19 , 20 , 21 , 22 , 60 , 61 , 62 ]. Both compounds show high affinity for the 5-HT 1A and D 2 receptors, a wider active dose range in the forced swim test than the tail suspension test, and antidepressant-like effect at lower doses than the reference antidepressants.…”

Section: Discussionmentioning

confidence: 99%

Synthesis and Evaluation of the Antidepressant-like Properties of HBK-10, a Novel 2-Methoxyphenylpiperazine Derivative Targeting the 5-HT1A and D2 Receptors

et al. 2021

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The increasing number of patients reporting depressive symptoms requires the design of new antidepressants with higher efficacy and limited side effects. As our previous research showed, 2-methoxyphenylpiperazine derivatives are promising candidates to fulfill these criteria. In this study, we aimed to synthesize a novel 2-methoxyphenylpiperazine derivative, HBK-10, and investigate its in vitro and in vivo pharmacological profile. After assessing the affinity for serotonergic and dopaminergic receptors, and serotonin transporter, we determined intrinsic activity of the compound at the 5-HT1A and D2 receptors. Next, we performed behavioral experiments (forced swim test, tail suspension test) to evaluate the antidepressant-like activity of HBK-10 in naïve and corticosterone-treated mice. We also assessed the safety profile of the compound. We showed that HBK-10 bound strongly to 5-HT1A and D2 receptors and presented antagonistic properties at these receptors in the functional assays. HBK-10 displayed the antidepressant-like effect not only in naïve animals, but also in the corticosterone-induced mouse depression model, i.e., chronic administration of HBK-10 reversed corticosterone-induced changes in behavior. Moreover, the compound’s sedative effect was observed at around 26-fold higher doses than the antidepressant-like ones. Our study showed that HBK-10 displayed a favorable pharmacological profile and may represent an attractive putative treatment candidate for depression.

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

Cited by 8 publications

References 35 publications

HBK-15, a Multimodal Compound, Showed an Anxiolytic-Like Effect in Rats

HBK-15, a Multimodal Compound, Showed an Anxiolytic-Like Effect in Rats

Single Administration of HBK-15—a Triple 5-HT1A, 5-HT7, and 5-HT3 Receptor Antagonist—Reverses Depressive-Like Behaviors in Mouse Model of Depression Induced by Corticosterone

Synthesis and Evaluation of the Antidepressant-like Properties of HBK-10, a Novel 2-Methoxyphenylpiperazine Derivative Targeting the 5-HT1A and D2 Receptors

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