Publications by authors named "Jacek Sapa"

83 Publications

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

Pharmaceuticals (Basel) 2021 Jul 29;14(8). Epub 2021 Jul 29.

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.

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-HT and D 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-HT and D 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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http://dx.doi.org/10.3390/ph14080744DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8400343PMC
July 2021

Metabolic benefits of novel histamine H receptor ligands in the model of excessive eating: The importance of intrinsic activity and pharmacokinetic properties.

Biomed Pharmacother 2021 Jul 26;142:111952. Epub 2021 Jul 26.

Department of Pharmacological Screening, Jagiellonian University, Medical College, Medyczna 9, PL 30-688 Cracow, Poland. Electronic address:

Aims: One of the therapeutic approaches in the treatment of obesity is the use of histamine H receptor ligands. Histamine plays a significant role in eating behavior because it causes a loss of appetite and is considered to be a satiety signal released during food intake.

Material And Methods: Histamine ligands were selected based on the preliminary studies which included determination of intrinsic activity and selected pharmacokinetic parameters. Female Wistar rats were fed palatable feed for 28 days and simultaneously the tested compounds were administered intraperitoneally at a dose of 10 mg/kg b.w./day. Rats' weight was evaluated daily and calories intake was evaluated once per week. At the end of experiment insulin and glucose tolerance tests was performed. Plasma levels of cholesterol, triglycerides, leptin, insulin, glucose, C-peptide and CRP were also determined. In order to rule out false-positive results the influence of tested compounds on spontaneous activity of rats was monitored.

Results: Animals fed palatable feed and treated with KSK-61 or KSK-63 compounds showed the slowest weight gain which was comparable to the one observed in control animals. Both compounds with the highest pharmacological activity have also similar pharmacokinetic properties with quite long half-life and high volume of distribution indicating that they can freely cross most biological barriers. Some compounds, especially KSK-63, compensated for metabolic disorders.

Conclusion: The presented study proves that search among the active histamine H receptor ligands for the new therapeutic agents to treat obesity is justified. Compounds KSK-61 and KSK-63 can be considered as the leading structures.
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http://dx.doi.org/10.1016/j.biopha.2021.111952DOI Listing
July 2021

Influence of betahistine repeated administration on a weight gain and selected metabolic parameters in the model of excessive eating in rats.

Biomed Pharmacother 2021 Sep 3;141:111892. Epub 2021 Jul 3.

Department of Pharmacological Screening, Jagiellonian University Medical College, Medyczna 9, PL 30-688 Cracow, Poland. Electronic address:

It is important to search for a promising therapeutic target or small molecules that can control excessive eating since limiting the intake of foods, especially tasty ones, could be effective in the treatment or prevention of obesity. Some studies indicate betahistine as an unique drug having the ability to ameliorate, for example, antipsychotic-induced weight gain. This study aimed to determine whether repeated administration of betahistine (histamine H1R agonist and H3R antagonist) could be beneficial in reducing the intake of tasty foods or the body's response to overeating via mechanisms such as by influencing the levels of hormones involved in the regulation of food intake or the levels of selected metabolic parameters. Studies were performed in the excessive eating model in rats, which perfectly illustrates the harmful high-caloric intake from freely available tasty products rich in sugar and fat. Our results indicated that repeated administration of betahistine to rats caused lower gain of body mass compared to the control rats fed palatable feed. Interestingly, betahistine treatment increased the consumption of cheese, which is a source of histamine. Although betahistine did not prevent the development of metabolic disorders, such as reduced glucose tolerance, in test animals, it significantly increased the level of high-density lipoprotein cholesterol, which could certainly be considered beneficial. Further studies should be conducted to investigate the effect of repeated administration of betahistine on satiety, gastrointestinal disorders, and the preference for histamine-containing foods.
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http://dx.doi.org/10.1016/j.biopha.2021.111892DOI Listing
September 2021

Design, Sustainable Synthesis and Biological Evaluation of a Novel Dual α2A/5-HT7 Receptor Antagonist with Antidepressant-Like Properties.

Molecules 2021 Jun 23;26(13). Epub 2021 Jun 23.

Department of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Kraków, Poland.

The complex pathophysiology of depression, together with the limits of currently available antidepressants, has resulted in the continuous quest for alternative therapeutic strategies. Numerous findings suggest that pharmacological blockade of α-adrenoceptor might be beneficial for the treatment of depressive symptoms by increasing both norepinephrine and serotonin levels in certain brain areas. Moreover, the antidepressant properties of 5-HT receptor antagonists have been widely demonstrated in a large set of animal models. Considering the potential therapeutic advantages in targeting both α-adrenoceptors and 5-HT receptors, we designed a small series of arylsulfonamide derivatives of (dihydrobenzofuranoxy)ethyl piperidines as dually active ligands. Following green chemistry principles, the designed compounds were synthesized entirely using a sustainable mechanochemical approach. The identified compound behaved as a potent α/5-HT receptor antagonist and displayed moderate-to-high selectivity over α-adrenoceptor subtypes and selected serotonin and dopaminergic receptors. Finally, compound improved performance of mice in the forced swim test, displaying similar potency to the reference drug mirtazapine.
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http://dx.doi.org/10.3390/molecules26133828DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8270334PMC
June 2021

MH-76, a Novel Non-Quinazoline α-Adrenoceptor Antagonist, but Not Prazosin Reduces Inflammation and Improves Insulin Signaling in Adipose Tissue of Fructose-Fed Rats.

Pharmaceuticals (Basel) 2021 May 18;14(5). Epub 2021 May 18.

Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

Background: Quinazoline α-adrenoceptors antagonists have been shown to exert moderately favorable effects on the metabolic profile in hypertensive patients. However, based on AntiHypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) results, they are no longer recommended as a first line therapy of hypertension. Recent studies have shown that quinazoline-based α-adrenoceptors antagonists (prazosin, doxazosin) induce the apoptosis and necrosis, which may be responsible for ALLHAT outcomes; however, these effects were proven to be independent of α-adrenoceptor blockade and were associated with the presence of quinazoline moiety. MH-76 (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride)) is a non-quinazoline α-adrenoceptor antagonist which, in fructose-fed rats, exerted antihypertensive effect, and, contrary to prazosin, reduced insulin resistance and abdominal adiposity. In this study we aimed to further investigate and compare the effects of MH-76 and prazosin on inflammation in adipose tissue of fructose-fed rats.

Methods: Abdominal adipose tissue was collected from four groups of fructose-fed rats (Control, Fructose, Fructose + MH-76 and Fructose + Prazosin) and subjected to biochemical, histopathological and immunohistochemical studies. Moreover, selected tissue distribution studies were performed.

Results: Treatment with MH-76 but not with prazosin improved endothelial integrity, reduced adipose tissue inflammation and infiltration by immune cells, resulting in lowering leptin, MCP-1, IL-6, TNF-α and PAI-1 levels. In adipose tissue from Fructose + MH-76 animals, a higher amount of eosinophils accompanied with higher IL-4 concentration was observed. Treatment with MH-76 but not with prazosin markedly reduced phosphorylation of IRS-1 at Ser307.

Conclusion: MH-76 may improve insulin signaling in adipose tissue by reducing the pro-inflammatory cytokine production and inhibiting the inflammatory cells recruitment. In contrast, in adipose tissue from animals treated with prazosin, the inflammatory effect was clearly enhanced.
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http://dx.doi.org/10.3390/ph14050477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8157569PMC
May 2021

Effects of GPR18 Ligands on Body Weight and Metabolic Parameters in a Female Rat Model of Excessive Eating.

Pharmaceuticals (Basel) 2021 Mar 16;14(3). Epub 2021 Mar 16.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University, Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

GPR18 has been proposed to play a role in the progression of metabolic disease and obesity. Therefore, the aim of this study was to determine the effects of selective GRP18 ligands (the antagonists PSB-CB5 and PSB-CB27 and the agonist PSB-KK1415) on body mass and the development of metabolic disorders commonly accompanying obesity. Experiments were carried out on female Wistar rats. In order to determine the anorectic activity of the investigated ligands, their effect on food and water intake in a model of excessive eating was assessed. Lipid profile, glucose and insulin levels as well as alanine aminotransferase, aspartate aminotransferase, and γ-glutamyl transpeptidase activity in plasma were also evaluated. Potential side effects were examined in rat models of pica behavior and conditioned taste aversion. Animals treated with different ligands gained significantly less weight than rats from the obese control group. Effects of GPR18 antagonists on food intake and body weight were specific and unrelated to visceral illness, stress or changes in spontaneous activity. However, the GPR18 agonist is likely to affect body weight by inducing gastrointestinal disorders such as nausea. The presented preliminary data support the idea that the search for selective GPR18 antagonists for the treatment of obesity might be promising.
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http://dx.doi.org/10.3390/ph14030270DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002110PMC
March 2021

PSB 603 - a known selective adenosine A2B receptor antagonist - has anti-inflammatory activity in mice.

Biomed Pharmacother 2021 Mar 29;135:111164. Epub 2020 Dec 29.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

A adenosine receptors are present in a wide spectrum of tissues, especially on cells of the immune system. Since these particular receptors have the lowest, of all adenosine receptor subtypes, affinity for adenosine they are believed to play a special role in immunological processes associated with elevated adenosine levels such as inflammation. The aim of this preliminary study was to determine the potential anti-inflammatory properties of compound PSB-603, a potent and selective adenosine A receptor antagonist, in two different experimental models of local and systemic inflammation. In a model of inflammation induced by local carrageenan administration paw edema was measured using a pletysmometer. Additionally, levels of C-reactive protein (CRP), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α) and reactive oxygen species (ROS) were determined in the inflamed paw. Using the mouse model of peripheral inflammation induced by intraperitoneal (ip) administration of zymosan A, the influence of the A antagonist on the infiltration of neutrophils into the peritoneum and its effect on the plasma levels of CRP, TNF-α, and IL-6 were investigated. The results showed that PSB-603 administered at a dose of 5 mg/kg b.w. ip significantly reduced inflammation in both tested models. Particularly, it significantly decreased levels of the inflammatory cytokines IL-6, TNF-α and of ROS in the inflamed paw and reduced inflammation of the peritoneum by significantly decreasing the infiltration of leukocytes. Additionally, in the latter model, no statistically significant difference was observed in the CRP level between the control group without inflammation and the group which has been treated with the PSB-603 compound. Thus, the results may indicate the anti-inflammatory activity of adenosine A receptor antagonists in two different models of inflammation.
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http://dx.doi.org/10.1016/j.biopha.2020.111164DOI Listing
March 2021

Bioresearch of New 1-pyrrolo[3,4-c]pyridine-1,3(2)-diones.

Molecules 2020 Dec 12;25(24). Epub 2020 Dec 12.

Department of Medicinal Chemistry, Faculty of Pharmacy, Wroclaw Medical University, Borowska 211, 50-556 Wroclaw, Poland.

The subject of the work was the synthesis of new derivatives of1-pyrrolo[3,4-c]pyridine-1,3(2)-dione with potential analgesic and sedative activity. Eight compounds werereceived. The analgesic activity of the new compounds was confirmed in the "hot plate" test and in the "writhing" test. All tested imides - were more active in the "writhing" test than aspirin, and two of them, and , were similar to morphine. In addition, all of the new imides inhibited the locomotor activity in mice to a statistically significant extent, and two of them also prolonged the duration of thiopental sleep.On the basis of the results obtained for the previously synthesized imides and the results presented in this paper, an attempt was madeto determine the relationship between thechemical structure of imides and their analgesic and sedativeproperties.
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http://dx.doi.org/10.3390/molecules25245883DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764601PMC
December 2020

The antidepressant-like activity of chiral xanthone derivatives may be mediated by 5-HT1A receptor and β-arrestin signalling.

J Psychopharmacol 2020 12 24;34(12):1431-1442. Epub 2020 Oct 24.

Department of Pharmacodynamics, Jagiellonian University Medical College, Kraków, Poland.

Background: Our previous studies showed that xanthone derivatives with -(2-methoxyphenyl)piperazine fragment have an affinity to the 5-HT1A receptor and show antidepressant-like properties in rodents. In this study, we tested three xanthone derivatives, HBK-1 and its enantiomers, in which we increased the distance between the piperazine and xanthone fragments by using a hydroxypropoxy linker. We hypothesized that this would increase the binding to the 5-HT1A receptor and consequently, pharmacological activity.

Aims: We aimed to assess the and pharmacological activity of the xanthone derivatives.

Methods: We evaluated the affinity for serotonin 5-HT1A and 5-HT2A receptors and serotonin transporter. We also determined the intrinsic activity at the 5-HT1A receptor. We investigated the antidepressant-like properties and safety after acute administration (dose range: 1.25-20 mg/kg) using the forced swim, tail suspension, locomotor activity, rotarod and chimney tests in mice. We also evaluated the basic pharmacokinetic parameters.

Results: Our results indicated that the compounds showed a high affinity for the 5-HT1A receptor but very weak antagonistic properties in the Ca mobilization assay; however, they showed significant agonistic properties in the β-arrestin recruitment assay. In both behavioural tests the studied xanthone derivatives showed antidepressant-like activity. Pre-treatment with p-chlorophenylalanine or WAY-100635 abolished their antidepressant-like activity. None of the compounds caused motor impairments at antidepressant-like doses. The racemate penetrated the blood-brain barrier and had a relatively high bioavailability after intraperitoneal administration.

Conclusions: Xanthone derivatives with -(2-methoxyphenyl)piperazine fragment and hydroxypropoxy linker show increased binding to the 5-HT1A receptor and may represent an attractive putative treatment candidate for depression.
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http://dx.doi.org/10.1177/0269881120959605DOI Listing
December 2020

Pitolisant protects mice chronically treated with corticosterone from some behavioral but not metabolic changes in corticosterone-induced depression model.

Pharmacol Biochem Behav 2020 09 19;196:172974. Epub 2020 Jun 19.

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland. Electronic address:

Purpose: Histamine H receptor ligands may have antidepressant and anxiolytic effects. They can also compensate for metabolic disorders, which affect glucose or triglyceride levels. In previous studies, we have shown that pitolisant, a histamine H receptor antagonist/inverse agonist and σ1 receptor agonist, prevented the development of certain metabolic and depressive-like disorders in mice that have been treated chronically with olanzapine.

Methods: As a continuation of our previous experiments, this study aimed to investigate the antidepressant- and anxiolytic-like activity of pitolisant in mice using the corticosterone-induced depression model. The forced swim and the elevated plus maze tests were used as behavioral endpoints. We also studied the effect pitolisant had on the level of acetoacetic acid in the urine as well as the glucose tolerance and body weight of the mice that had been administered corticosterone.

Results: Pitolisant (10 mg/kg b.w.) did not prevent depressive-like behavior in mice during the chronic corticosterone administration but did counteract anxiety-like behavior, whilst fluoxetine (10 mg/kg) was shown to protect the mice from both of these behaviors. None of the treatments that were used in the study showed an effect on the locomotor activity of the mice. Pitolisant did not prevent an increase in acetoacetic acid levels in the urine, nor did it improve glucose tolerance in the tested mice.

Conclusion: Although literature data indicates that there is significant potential for finding an antidepressant and anti-diabetic drug among the histamine H and σ1 receptor ligands, in our study, pitolisant was shown to only slightly compensate for corticosterone-induced abnormalities. However, further research will be required to study pitolisant's anxiolytic-like activity.
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http://dx.doi.org/10.1016/j.pbb.2020.172974DOI Listing
September 2020

KD-64-A new selective A2A adenosine receptor antagonist has anti-inflammatory activity but contrary to the non-selective antagonist-Caffeine does not reduce diet-induced obesity in mice.

PLoS One 2020 18;15(6):e0229806. Epub 2020 Jun 18.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

The A2 adenosine receptors play an important role, among others, in the regulation of inflammatory process and glucose homeostasis in diabetes and obesity. Thus, the presented project evaluated of influence of the selective antagonist of A2A adenosine receptor-KD-64 as compared to the known non-selective antagonist-caffeine on these two particular processes. Two different inflammation models were induced namely local and systemic inflammation. Obesity was induced in mice by high-fat diet and the tested compounds (KD-64 and caffeine) were administrated for 21 days. KD-64 showed anti-inflammatory effect in both tested inflammation models and administered at the same dose as ketoprofen exerted stronger effect than this reference compound. Elevated levels of IL-6 and TNF-α observed in obese control mice were significantly lowered by the administration of KD-64 and were similar to the values observed in control non-obese mice. Interestingly, caffeine increased the levels of these parameters. In contrast to caffeine which had no influence on AlaT activity, KD-64 administration significantly lowered AlaT activity in the obese mice. Although, contrary to caffeine, KD-64 did not reduce diet-induced obesity in mice, it improved glucose tolerance. Thus, the activity of the selective adenosine A2A receptor antagonist was quite different from that of the non-selective.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0229806PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7302451PMC
August 2020

KSK19 - Novel histamine H3 receptor ligand reduces body weight in diet induced obese mice.

Biochem Pharmacol 2019 10 8;168:193-203. Epub 2019 Jul 8.

Department of Pharmacological Screening, Jagiellonian University Medical College, 9 Medyczna Street, PL 30-688 Krakow, Poland.

Aims: Histamine H receptors ligands act anorectic by blocking the H autoreceptors in the CNS, that results in increased synthesis and disinhibition of histamine release. Histamine further influencing H receptors participates in the leptin-dependent inhibition of food intake. It also affects the peripheral metabolism by increasing white adipose tissue lipolysis. Thus, ligands such as KSK19 with significant antagonistic properties at the H receptor might serve as an useful treatment for obesity.

Materials And Methods: To induce obesity, female CD-1 mice were fed a high-fat diet for 14 weeks. The test compound at the doses of 10 or 15 mg/kg, i.p. was administrated for 21 days. Glucose and insulin tolerance tests was performed at the beginning of week 15. At the end of study, amount of intraperitoneal fat pads, AlAT, IL-6 and TNF-α plasma levels were determined.

Results: Animals fed with high-fat diet and treated with test compound at the dose of 15 mg/kg showed significantly less weight gain, than mice from the control group. The use of KSK19 for 21 days in obese mice also significantly improved glucose tolerance and insulin resistance. In the tested doses KSK19 did not affect locomotor activity neither in lean nor in obese mice after single i.p. administration, but spontaneous activity increased during three hour after twentieth administrations.

Conclusion: KSK19 is a strong, selective histamine H receptor antagonist with a favorable influence on body weight after multiple administration at the dose of 15 mg/kg. Moreover it significantly improves glucose tolerance.
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http://dx.doi.org/10.1016/j.bcp.2019.07.006DOI Listing
October 2019

The Significance of Lactoperoxidase System in Oral Health: Application and Efficacy in Oral Hygiene Products.

Int J Mol Sci 2019 Mar 21;20(6). Epub 2019 Mar 21.

Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Kraków, Poland.

Lactoperoxidase (LPO) present in saliva are an important element of the nonspecific immune response involved in maintaining oral health. The main role of this enzyme is to oxidize salivary thiocyanate ions (SCN) in the presence of hydrogen peroxide (H₂O₂) to products that exhibit antimicrobial activity. LPO derived from bovine milk has found an application in food, cosmetics, and medical industries due to its structural and functional similarity to the human enzyme. Oral hygiene products enriched with the LPO system constitute an alternative to the classic fluoride caries prophylaxis. This review describes the physiological role of human salivary lactoperoxidase and compares the results of clinical trials and in vitro studies of LPO alone and complex dentifrices enriched with bovine LPO. The role of reactivators and inhibitors of LPO is discussed together with the possibility of using nanoparticles to increase the stabilization and activity of this enzyme.
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http://dx.doi.org/10.3390/ijms20061443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6472183PMC
March 2019

HBK-17, a 5-HT Receptor Ligand With Anxiolytic-Like Activity, Preferentially Activates ß-Arrestin Signaling.

Front Pharmacol 2018 16;9:1146. Epub 2018 Oct 16.

Department of Bioorganic Chemistry, Chair of Organic Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

Numerous studies have proven that both stimulation and blockade of 5-HT and the blockade of 5-HT receptors might cause the anxiolytic-like effects. Biased agonists selectively activate specific signaling pathways. Therefore, they might offer novel treatment strategies. In this study, we investigated the anxiolytic-like activity, as well as the possible mechanism of action of 1-[(2,5-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-17). In our previous experiments, HBK-17 showed high affinity for 5-HT and 5-HT receptors and antidepressant-like properties. We performed the four plate test and the elevated plus maze test to determine anxiolytic-like activity. Toward a better understanding of the pharmacological properties of HBK-17 we used various functional assays to determine its intrinsic activity at 5-HT, 5-HT, 5-HT, and D receptors and UHPLC-MS/MS method to evaluate its pharmacokinetic profile. We observed the anxiolytic-like activity of HBK-17 in both behavioral tests and the effect was reversed by the pretreatment with WAY-100635, which proves that 5-HT receptor activation was essential for the anxiolytic-like effect. Moreover, the compound moderately antagonized D, weakly 5-HT and very weakly 5-HT receptors. We demonstrated that HBK-17 preferentially activated ß-arrestin signaling after binding to the 5-HT receptor. HBK-17 was rapidly absorbed after intraperitoneal administration and had a half-life of about 150 min. HBK-17 slightly penetrated the peripheral compartment and showed bioavailability of approximately 45%. The unique pharmacological profile of HBK-17 encourages further experiments to understand its mechanism of action fully.
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http://dx.doi.org/10.3389/fphar.2018.01146DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6209770PMC
October 2018

Correlation of Paraoxonase-1 with the Severity of Crohn's Disease.

Molecules 2018 Oct 11;23(10). Epub 2018 Oct 11.

Department of Medical Diagnostics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.

Diagnostics of Crohn's disease (CD) requires noninvasive biomarkers facilitating early detection and differentiation of the disease. Therefore, in this study, we aimed to determine the relationship between paraoxonase-1 (PON-1), the severity of CD, oxidative stress, and inflammation in CD. The CD activity index was based on the current classification. Plasma PON-1 was measured in 47 patients with CD, and in 23 control volunteers. Using quantitative variables such as receiver operating characteristics (ROC) (area under the curve (AUC)), the diagnostic utility of PON-1 in differentiating the severity of CD was assessed. Circulating PON-1 was found to be decreased in the CD group compared to the control group (269.89 vs. 402.56 U/L, respectively), and it correlated well with the disease activity. PON-1 correlated positively with hemoglobin (Hb) (r = 0.539, < 0.001), hematocrit (Ht) (r = 0.48, < 0.001), total cholesterol (TC) (r = 0.343, < 0.001), high density lipoprotein (HDL) (r = 0.536, < 0.001), low density lipoprotein (LDL) (r = 0.54, < 0.001), and triglyceride (TG) (r = 0.561, < 0.001) and correlated negatively with white blood cell count (WBC) (r = -0.262, p = 0.029), platelet count (PLT) (r = -0.326, p = 0.006), C-reactive protein (CRP) (r = -0.61, < 0.001), and malondialdehyde (MDA) (r = -0.924, < 0.001). PON-1 as a marker for CD differentiation possessed a sensitivity and specificity of 93.62% and 91.30%, respectively. CD was found to be associated with the decrease in the levels of PON-1, which correlates well with activity of the disease and reflects the intensification of inflammation, as well as intensified lipid peroxidation. High sensitivity and specificity of PON-1 determines its selection as a good screening test for CD severity.
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http://dx.doi.org/10.3390/molecules23102603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6222603PMC
October 2018

Synthesis and Pharmacological Evaluation of Novel Silodosin-Based Arylsulfonamide Derivatives as α/α-Adrenergic Receptor Antagonist with Potential Uroselective Profile.

Molecules 2018 Aug 29;23(9). Epub 2018 Aug 29.

Department of Medicinal Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Krakow, Poland.

Benign prostatic hyperplasia (BPH) is the most common male clinical problem impacting the quality of life of older men. Clinical studies have indicated that the inhibition of α-/α adrenoceptors might offer effective therapy in lower urinary tract symptoms. Herein, a limited series of arylsulfonamide derivatives of (aryloxy)ethyl alicyclic amines was designed, synthesized, and biologically evaluated as potent α₁-adrenoceptor antagonists with uroselective profile. Among them, compound (3-chloro-2-fluoro--([1-(2-(2-(2,2,2-trifluoroethoxy)phenoxy]ethyl)piperidin-4-yl)methyl)benzenesulfonamide) behaved as an α-/α-adrenoceptor antagonist ((α₁) = 50 nM, EC(α) = 0.8 nM, EC(α) = 1.1 nM), displayed selectivity over α₂-adrenoceptors ((α₂) = 858 nM), and a 5-fold functional preference over the α subtype. Compound showed adequate metabolic stability in rat-liver microsome assay similar to the reference drug tamsulosin (Cl = 67 and 41 µL/min/mg, respectively). Compound did not decrease systolic and diastolic blood pressure in normotensive anesthetized rats in the dose of 2 mg/kg, . These data support development of uroselective agents in the group of arylsulfonamides of alicyclic amines with potential efficacy in the treatment of lower urinary tract symptoms associated to benign prostatic hyperplasia.
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http://dx.doi.org/10.3390/molecules23092175DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6225212PMC
August 2018

Serotonin receptors in depression and anxiety: Insights from animal studies.

Life Sci 2018 Oct 23;210:106-124. Epub 2018 Aug 23.

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland. Electronic address:

Serotonin regulates many physiological processes including sleep, appetite, and mood. Thus, serotonergic system is an important target in the treatment of psychiatric disorders, such as major depression and anxiety. This natural neurotransmitter interacts with 7 families of its receptors (5-HT1-7), which cause a variety of pharmacological effects. Using genetically modified animals and selective or preferential agonists and antagonist, numerous studies demonstrated the involvement of almost all serotonin receptor subtypes in antidepressant- or anxiolytic-like effects. In this review, based on animal studies, we discuss the possible involvement of serotonin receptor subtypes in depression and anxiety.
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http://dx.doi.org/10.1016/j.lfs.2018.08.050DOI Listing
October 2018

The histamine H receptor inverse agonist pitolisant reduces body weight in obese mice.

Naunyn Schmiedebergs Arch Pharmacol 2018 08 25;391(8):875-881. Epub 2018 May 25.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

The pharmacological profile of pitolisant, a histamine H receptor antagonist/inverse agonist, indicates that this compound might reduce body weight and metabolic disturbances. Therefore, we studied the influence of pitolisant on body weight, water and sucrose intake as well as metabolic disturbances in the high-fat and high-sugar diet-induced obesity model in mice. To induce obesity, male CD-1 mice were fed a high-fat diet consisting of 40% fat blend for 14 weeks, water and 30% sucrose solution available ad libitum. Glucose tolerance test was performed at the beginning of week 15. Insulin tolerance was tested the day after. At the end of study, plasma levels of triglycerides and cholesterol were determined. Pitolisant at dose of 10 mg/kg bw (ip) was administrated during 14 days, starting from the beginning of week 13. Metformin at dose of 100 mg/kg bw (ip) was used as reference drug. Mice fed with high-fat diet and sucrose solution showed more weight gain throughout the 12-week period of inducing obesity. Animals fed with high-fat diet and treated with pitolisant (for the next 14 days) showed significantly less weight gain than mice from the control group consuming a high-fat feed. In the group treated with pitolisant, glucose levels were significantly lower than glucose levels of control obese mice after glucose load. The plasma triglyceride levels in pitolisant-treated mice were significantly lower compared with those in control obese group. In conclusion, pitolisant has a favorable influence of body weight and improves glucose tolerance and the lipid profile in obese mice.
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http://dx.doi.org/10.1007/s00210-018-1516-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6061715PMC
August 2018

Synthesis and biological evaluation of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential antiplatelet agents.

J Enzyme Inhib Med Chem 2018 Dec;33(1):536-545

a Department of Medicinal Chemistry , Jagiellonian University Medical College , Kraków , Poland.

Despite the substantial clinical success of aspirin and clopidogrel in secondary prevention of ischemic stroke, up to 40% of patients remain resistant to the available antiplatelet treatment. Therefore, there is an urgent clinical need to develop novel antiplatelet agents with a novel mechanism of action. Recent studies revealed that potent alpha 2B-adrenergic receptor (alpha 2B-ARs) antagonists could constitute alternative antiplatelet therapy. We have synthesized a series of N-arylpiperazine derivatives of 4,4-dimethylisoquinoline-1,3(2H,4H)-dione as potential alpha 2B receptor antagonists. The most potent compound 3, effectively inhibited the platelet-aggregation induced both by collagen and ADP/adrenaline with IC of 26.9 μM and 20.5 μM respectively. Our study confirmed that the alpha 2B-AR antagonists remain an interesting target for the development of novel antiplatelet agents with an alternative mechanism of action.
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http://dx.doi.org/10.1080/14756366.2018.1437155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010133PMC
December 2018

The role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in antidepressant-like effect.

Pharmacol Rep 2017 May 29;69(3):546-554. Epub 2017 Jan 29.

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.

Over the last few decades, depression has become one of the major public health problems in our society. This problem is connected not only with morbidity, but also with treatment, specifically with the effectiveness of the therapy as well as the concomitant side effects of available antidepressants. Major depressive disorder is a complex clinical entity, including different molecular mechanisms and neurological processes. This complexity is a challenge for scientists seeking to discover an innovatory antidepressant drug with multiple and complementary mechanisms of action. In this review, we discuss the role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in depression and antidepressant-like effects.
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http://dx.doi.org/10.1016/j.pharep.2017.01.026DOI Listing
May 2017

The role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in antidepressant-like effect.

Pharmacol Rep 2017 Jun 29;69(3):546-554. Epub 2017 Jan 29.

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.

Over the last few decades, depression has become one of the major public health problems in our society. This problem is connected not only with morbidity, but also with treatment, specifically with the effectiveness of the therapy as well as the concomitant side effects of available antidepressants. Major depressive disorder is a complex clinical entity, including different molecular mechanisms and neurological processes. This complexity is a challenge for scientists seeking to discover an innovatory antidepressant drug with multiple and complementary mechanisms of action. In this review, we discuss the role of melatonin, neurokinin, neurotrophic tyrosine kinase and glucocorticoid receptors in depression and antidepressant-like effects.
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http://dx.doi.org/10.1016/j.pharep.2017.01.026DOI Listing
June 2017

Evaluation of antidepressant-like and anxiolytic-like activity of purinedione-derivatives with affinity for adenosine A receptors in mice.

Pharmacol Rep 2016 Dec 25;68(6):1285-1292. Epub 2016 Jul 25.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.

Background: It has recently been suggested that the adenosine A receptor plays a role in several animal models of depression. Additionally, A antagonists have reversed behavioral deficits and exhibited a profile similar to classical antidepressants.

Methods: In the present study, imidazo- and pyrimido[2,1-f]purinedione derivatives (KD 66, KD 167, KD 206) with affinity to A receptors but poor A affinity were evaluated for their antidepressant- and anxiolytic-like activity. The activity of these derivatives was tested using a tail suspension and forced swim test, two widely-used behavioral paradigms for the evaluation of antidepressant-like activity. In turn, the anxiolytic activity was evaluated using the four-plate test.

Results: The results showed the antidepressant-like activity of pyrimido- and imidazopurinedione derivatives (i.e. KD 66, KD 167 and KD 206) in acute and chronic behavioral tests in mice. KD 66 revealed an anxiolytic-like effect, while KD 167 increased anxiety behaviors. KD 206 had no effect on anxiety. Furthermore, none of the tested compounds increased locomotor activity.

Conclusion: Available data support the proposition that the examined compounds with adenosine A receptor affinity may be an interesting target for the development of antidepressant and/or anxiolytic agents.
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http://dx.doi.org/10.1016/j.pharep.2016.07.008DOI Listing
December 2016

Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α-adrenergic receptor antagonist with uro-selective activity.

Bioorg Med Chem 2016 11 10;24(21):5582-5591. Epub 2016 Sep 10.

Department of Pharmacological Screening, Faculty of Pharmacy, Jagiellonian University Medical College, 9 Medyczna Street, 30-688 Kraków, Poland.

A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α-adrenoceptor antagonists with uroselective profile. Biological evaluation for α- and α-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α-adrenoceptor (K=34-348nM) and moderate selectivity over α-receptor subtype. Compounds with highest affinity and selectivity for α-adrenoceptor were evaluated in vitro for their intrinsic activity toward α- and α-adrenoceptor subtypes. All compounds behaved as antagonists at both α-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α-subtype. Among them, N-{1-[2-(2-methoxyphenoxy)ethyl]piperidin-4-yl}isoquinoline-4-sulfonamide (25) and 3-chloro-2-fluoro-N-{[1-(2-(2-isopropoxyphenoxy)ethyl)piperidin-4-yl]methyl}benzene sulfonamide (34) displayed the highest preference to α-adrenoceptor. Finally, compounds 25 and 34 (2-5mg/kg, iv), in contrast to tamsulosin (1-2mg/kg, iv), did not significantly decrease systolic and diastolic blood pressure in normotensive anesthetized rats to determine their influence on blood pressure.
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http://dx.doi.org/10.1016/j.bmc.2016.09.017DOI Listing
November 2016

Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats.

Front Pharmacol 2016 3;7:229. Epub 2016 Aug 3.

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College Krakow, Poland.

Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values-it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18-0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties. Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e., HBK-16, HBK-17, HBK-18, and HBK-19) were the most active compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia.
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http://dx.doi.org/10.3389/fphar.2016.00229DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4971072PMC
August 2016

ANTI-INFLAMMATORY AND ANTIOXIDANT ACTIVITY OF 8-METHOXY-1,3-DIMETHYL-2,6-DIOXO-PURIN-7-YL DERIVATIVES WITH TERMINAL CARBOXYLIC, ESTER OR AMIDE MOIETIES IN ANIMAL MODELS.

Acta Pol Pharm 2016 May-Jun;73(3):761-70

The previous studies in a series of 8-methoxy-1,3-dimethyl-2,6-dioxo-purin-7-yl derivatives revealed their analgesic properties. We extended the study with these compounds in aim to assess their impact on inflammatory process. For this purpose we used: the zymosan-induced peritonitis and the carrageenan-induced edema model. Furthermore, the antioxidant activity of the investigated compounds by the FRAP assay was determined. For the most active derivatives from evaluated series their influence on plasma TNF-α level was also tested in vivo. All investigated purine-2,6-dione derivatives 1-11 decreased neutrophils count and inhibited intensity of early vascular permeability. Furthermore, all evaluated compounds reduced the volume of edema caused by subcutaneous injection of carrageenan. Derivatives 1 (with ester moiety), 3 and 4 (with carboxylic group) showed the highest activity in the zymosan-induced peritonitis. In addition, a significant inhibition of plasma TNF-α level in rats with endotoxemia was observed following intraperitoneal administration of these compounds. In turn, compounds 6 and 8-11 containing amide moiety showed the greatest anti-inflammatory (antiedematous) effect in the carrageenan-induced paw edema model. All compounds did not show significant antioxidant properties. The present studies revealed that the presented purine-2,6-dione derivatives exhibit a significant anti-inflammatory activity and this effect may result from their ability to lower TNF-α level.
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September 2016

Design, synthesis, anticonvulsant, and antiarrhythmic properties of novel N-Mannich base and amide derivatives of β-tetralinohydantoin.

Pharmacol Rep 2016 Oct 21;68(5):886-93. Epub 2016 May 21.

Department of Medicinal Chemistry, Jagiellonian University Medical College, 9 Medyczna Str, 30-688 Kraków, Poland.

Background: 5,5-Diphenylhydantoin (Phenytoin) is a well-known anticonvulsant and antiarrhythmic drug which may cause unwanted side effects. In order to avoid the adverse effects of phenytoin, especially on the central nervous and cardiovascular systems, two small series of amine derivatives (Mannich bases) and amide ones were designed containing β-tetralinohydantoin system. In preliminary studies, some of arylpiperazinylmethyl derivatives with a β-tetralinohydantoin moiety were effective in screening anticonvulsant tests in mice.

Methods: These new amine and amide derivatives of β-tetralinohydantoin were evaluated in standard anticonvulsant screens (maximal electroshock (MES) or pentylenetetrazole (scPTZ) seizure tests) and their neurotoxicity was assessed in standardized rotarod tests. Additionally, due to structural features (a hydantoin ring), influence on antiarrhythmic activity, electrocardiogram components and blood pressure was tested in rats.

Results: The new N-Mannich bases were effective in maximal electroshock or pentylenetetrazole seizures screens; and the most interesting compound 4 (1-{[4-(1-phenyethyl)-piperazin-1-yl]methyl}-3',4'-dihydro-1'H,2H,5H-spiro[imidazolidine-4,2'-naphthalene]-2,5-dione) displayed anticonvulsant activity in both the aforementioned tests. Furthermore, compound 6, an amide derivative of β-tetralinohydantoin, displayed significant antiarrhythmic activity in a barium chloride-induced arrhythmia model (ED50 16.3mg/kg), but it was devoid of anticonvulsant protection. None of the tested compounds affected the electrocardiogram components or blood pressure in normotensive rats.

Conclusion: All new N-Mannich bases containing the β-tetralinohydantoin system and 1-phenylalkylpiperazine were classified to Anticonvulsant Screening Program 1st class. In contrast, our results suggested that the introduction of an amide bond in the alkyl side chain of the β-tetralinohydantoin system abolished the anticonvulsant activity, but not the antiarrhythmic one. However, further studies are required for a definitive conclusion.
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http://dx.doi.org/10.1016/j.pharep.2016.04.018DOI Listing
October 2016

The antidepressant- and anxiolytic-like activities of new xanthone derivative with piperazine moiety in behavioral tests in mice.

Indian J Pharmacol 2016 May-Jun;48(3):286-91

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, 30-688 Krakow, Poland.

Objectives: Xanthones are flavonoids with numerous activities, including antioxidant, antidepressant., or anxiolytic-like. Therefore, the aim of our study was to determine antidepressant- and anxiolytic-like properties of four xanthone derivatives (3-chloro-5-[(4-methylpiperazin-1-yl)methyl]-9H-xanthen-9-one dihydrochloride [HBK-5], 6-methoxy-2-[(4-methylpiperazin-1-yl) methyl]-9H-xanthen-9-one dihydrochloride, 2-[(4-benzylpiperazin-1-yl) methyl]-6-methoxy-9H-xanthen-9-one dihydrochloride, 2-{[4-(2-methoxyphenyl) piperazin-1-yl] methyl}-9H-xanthen-9-one hydrochloride), as well as the influence on cognitive and motor function of active compounds, using animal models.

Materials And Methods: To determine the antidepressant-like activity, we used forced swim test (FST) and tail suspension test (TST) in mice. We evaluated anxiolytic-like properties in the four-plate test in mice. We studied the influence on cognitive and motor function in passive avoidance step-through and chimney tests, respectively.

Results: The antidepressant-like activity (in both FST and TST) showed only HBK-5. Moreover, the compound was also active in the four-plate test, which suggests that it possessed anxiolytic-like properties. HBK-5 did not cause any cognitive and motor deficits in mice at antidepressant- and anxiolytic-like doses.

Conclusions: HBK-5 may have potential in the treatment of depression or anxiety disorders, but this issue needs further studies.
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http://dx.doi.org/10.4103/0253-7613.182872DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4900002PMC
May 2017

H3 histamine receptor antagonist pitolisant reverses some subchronic disturbances induced by olanzapine in mice.

Metab Brain Dis 2016 10 24;31(5):1023-9. Epub 2016 May 24.

Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Krakow, Poland.

The use of atypical antipsychotic drugs like olanzapine is associated with side effects such as sedation and depression-like symptoms, especially during the initial period of the use. It is believed that the occurrence of these undesirable effectsis mainly the result of the histamine H1receptors blockade by olanzapine. In addition, use of olanzapine increases the level of triglycerides in the blood, which correlates with growing obesity. The aim of this study was to investigate the influence of pitolisant - H3 histamine antagonist - on subchronic olanzapine-induced depresion-like symptoms, sedation and hypertriglicerydemia. Forced swim test was conducted to determinate depressive-like effect of olanzapine and antidepressive-like activity during the co-administered pitolisant. The test was performed after the first and fifteenth day of the treatment of the mice. The spontaneous activity of the mice was measured on the fourteenth day of the treatment with a special, innovative RFID-system (Radio-frequency identification system) - TraffiCage (TSE-Systems, Germany). Triglyceride levels were determined on the sixteenth day of the experiment after 15 cycles of drug administration. Daily olanzapine treatment (4 mg/kg b.w., i.p., d.p.d) for 15 days significantly induces sedation (p < 0.05) and prolongs immobility time in forced swim tests (FST) in mice (p < 0.05); and also elevates the level of triglycerides (p < 0.05). Administration of pitolisant (10 mg/kg b.w., i.p.) subsequentto olanzapine normalizes these adverse effects. This study presents a promising alternative for counteracting some behavioral changes and metabolic disturbances which occur in the early period of treatment with antipsychotic drugs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5031740PMC
http://dx.doi.org/10.1007/s11011-016-9840-zDOI Listing
October 2016

PRELIMINARY EVALUATION OF CENTRAL NERVOUS SYSTEM ACTIVITY OF (E)-N-2-METHYL-3-PHENYLPROP-2-ENYL ((E)-N- α-METHYLCINNAMYL) DERIVATIVES OF SELECTED AMINOALKANOLS.

Acta Pol Pharm 2016 Mar-Apr;73(2):345-57

A series of (E)-α-methylcinnamyl derivatives of selected aminoalkanols was synthetized and evaluated for activity in central nervous system. All compounds were tested as anticonvulsants and one additionally in antidepressant- and anxiolytic-like assays. The compounds possessed pharmacophoric elements regarded as beneficial for anticonvulsant activity: hydrophobic unit and two hydrogen bonds donor/acceptor features. The compounds were verified in mice after intraperitoneal (i.p.) administration in maximal electroshock (MES) and subcutaneous pentetrazole (scPTZ) induced seizures as well as neurotoxicity assessments. Eight of the tested substances showed protection in MES test at the dose of 100 mg/kg. The derivative of 2-aminopropan-1-ol was also tested in 6-Hz test in mice i.p. and showed anticonvulsant activity but at the same time the neurotoxicity was noted. The derivative of 2-amino-1-phenylethanol which possessed additional hydrophobic unit in aminoalkanol moiety was tested in other in vivo assays to evaluate antidepressant- and anxiolytic-like activity. The compound proved beneficial properties especially as anxiolytic agent remaining active in four-plate test in mice at the dose of 2.5 mg/kg (i.p.). In vitro biotransformation studies of 2-amino-1-phenylethanol derivative carried out in mouse liver microsomal assay indicated two main metabolites as a result of aliphatic and aromatic hydroxylation or aliphatic carbonylation. To identify possible mechanism of action, we evaluated serotonin receptors (5-HT1A, 5-HT6 and 5-HT7) binding affinities of the compounds but none of them proved to bind to any of tested receptors.
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June 2016

HBK-7 - A new xanthone derivative and a 5-HT1A receptor antagonist with antidepressant-like properties.

Pharmacol Biochem Behav 2016 Jul-Aug;146-147:35-43. Epub 2016 Apr 27.

Department of Pharmacodynamics, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland.

Xanthone derivatives possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study we aimed to investigate antidepressant- and anxiolytic-like properties of a new xanthone derivative - 6-methoxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-7), as well as its possible mechanism of action, and the influence on cognitive and motor function. HBK-7 in our earlier studies showed high affinity for serotonergic 5-HT1A receptor. We determined the affinity of HBK-7 for CNS receptors and transporters using radioligand assays and examined its intrinsic activity towards 5-HT1A receptor. We evaluated antidepressant- and anxiolytic-like activity of HBK-7 in the mouse forced swim test, and four-plate test, respectively. We examined the influence on locomotor activity in mice to determine if the effect observed in the forced swim test was specific. We used step-through passive avoidance and rotarod tests to evaluate the influence of HBK-7 on cognitive and motor function, respectively. HBK-7 showed moderate affinity for dopaminergic D2 receptor and very low for serotonergic 5-HT2A, adrenergic α2 receptors, as well as serotonin transporter. Functional studies revealed that HBK-7 was a 5-HT1A receptor antagonist. HBK-7 (10mg/kg) decreased immobility time in the forced swim test. Combined treatment with sub-effective doses of HBK-7 and fluoxetine reduced immobility of mice in the forced swim test. Pretreatment with p-chlorophenylalanine and WAY-100,635 antagonized the antidepressant-like effect of HBK-7. Neither of the treatments influenced locomotor activity of mice. HBK-7 at antidepressant-like dose did not impair memory or motor coordination in mice. We demonstrated that HBK-7 was a 5-HT1A receptor antagonist with potent, comparable to mianserin, antidepressant-like activity. HBK-7 mediated its effect through serotonergic system and its antidepressant-like action required the activation of 5-HT1A receptors. At active dose it did not influence cognitive and motor function. Since 5-HT1A receptor antagonists may accelerate the occurrence of antidepressant effect, our findings highlight their potential as future antidepressants.
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http://dx.doi.org/10.1016/j.pbb.2016.04.005DOI Listing
April 2017
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