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

Pytka, Karolina; Gawlik, Katarzyna; Pawlica-Gosiewska, Dorota; Witalis, Jadwiga; Waszkielewicz, Anna M.

doi:10.1007/s11011-016-9932-9

Cited by 17 publications

(21 citation statements)

References 37 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Since HBK-14 is stronger 5-HT 7 receptor antagonist, its anxiolytic-like effect might be more profound. These findings are consistent with our previous experiments, where we demonstrated that among the two, HBK-14 possessed stronger anxiolytic-like properties, whereas HBK-15 antidepressant-like activity [ 21 , 22 ]. The second explanation is simply the difference in bioavailability—HBK-14 has lower bioavailability, and this might underlie the lack of antidepressant-like effect.…”

Section: Discussionsupporting

confidence: 93%

“…Our previous experiments revealed that chronic treatment with HBK-15 increased serotonin level in the hippocampus [ 22 ]. Serotonin, at least partially, regulates the level of neurotrophins in the central nervous system [ 47 , 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…The doses and route of administration of the studied compounds were based on our previous experiments [ 21 , 22 ]. Since antidepressant-like activity of HBK-14 and HBK-15 was due to the interaction with serotonergic (not adrenergic) system [ 21 ], we chose fluoxetine (selective serotonin reuptake inhibitor) as reference drug.…”

Section: Methodsmentioning

confidence: 99%

“…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and very weakly 5-HT 2A receptors (IC 50 = 4459 nM), it did not show antipsychotic-like or cataleptogenic properties (unpublished results).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%

“…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%

See 4 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Self Cite

View full text Add to dashboard Cite

show abstract

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

et al. 2021

View full text Add to dashboard Cite

Depression is the single largest contributor to global disability with a huge economic and social burden on the world. There are a number of antidepressant drugs on the market, but treatment‐resistant depression and relapse of depression in a large number of patients have increased problems for clinicians. One peculiarity observed in most of the marketed antidepressants is the presence of a piperazine substructure. Although piperazine is also used in the optimization of other pharmacological agents, it is almost extensively used for the development of novel antidepressants. One common understanding is that this is due to its favorable CNS pharmacokinetic profile; however, in the case of antidepressants, piperazine plays a much bigger role and is involved in specific binding conformations of these agents. Therefore, in this review, a critical analysis of the significance of the piperazine moiety in the development of antidepressants has been performed. An overview of current developments in the designing and synthesis of piperazine‐based antidepressants (2015 onwards) along with SAR studies is also provided. The various piperazine‐based therapeutic agents in early‐ or late‐phase human testing for depression are also discussed. The preclinical compounds discussed in this review will help researchers understand how piperazine actually influences the design and development of novel antidepressant compounds. The SAR studies discussed will provide crucial clues about the structural features and optimizations required to enhance the efficacy and potency of piperazine‐based antidepressants.

show abstract

The effect of SSRIs on fear learning: a systematic review and meta-analysis

et al. 2023

View full text Add to dashboard Cite

Rationale Selective serotonin reuptake inhibitors (SSRIs) are considered first-line medication for anxiety-like disorders such as panic disorder, generalized anxiety disorder, and post-traumatic stress disorder. Fear learning plays an important role in the development and treatment of these disorders. Yet, the effect of SSRIs on fear learning are not well known. Objective We aimed to systematically review the effect of six clinically effective SSRIs on acquisition, expression, and extinction of cued and contextual conditioned fear. Methods We searched the Medline and Embase databases, which yielded 128 articles that met the inclusion criteria and reported on 9 human and 275 animal experiments. Results Meta-analysis showed that SSRIs significantly reduced contextual fear expression and facilitated extinction learning to cue. Bayesian-regularized meta-regression further suggested that chronic treatment exerts a stronger anxiolytic effect on cued fear expression than acute treatment. Type of SSRI, species, disease-induction model, and type of anxiety test used did not seem to moderate the effect of SSRIs. The number of studies was relatively small, the level of heterogeneity was high, and publication bias has likely occurred which may have resulted in an overestimation of the overall effect sizes. Conclusions This review suggests that the efficacy of SSRIs may be related to their effects on contextual fear expression and extinction to cue, rather than fear acquisition. However, these effects of SSRIs may be due to a more general inhibition of fear-related emotions. Therefore, additional meta-analyses on the effects of SSRIs on unconditioned fear responses may provide further insight into the actions of SSRIs.

show abstract

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

Cited by 17 publications

References 37 publications

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

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

Piperazine, a Key Substructure for Antidepressants: Its Role in Developments and Structure‐Activity Relationships

The effect of SSRIs on fear learning: a systematic review and meta-analysis

Contact Info

Product

Resources

About