Publications by authors named "Marek Bednarski"

57 Publications

The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects.

Pharmaceuticals (Basel) 2021 Aug 13;14(8). Epub 2021 Aug 13.

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

GPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of selective GPR18 receptor ligands, namely PSB-KD-107 (agonist) and PSB-CB-92 (antagonist), on blood pressure, electrocardiogram (ECG), and vascular dilatation in vitro and in vivo, as well as their anti-oxidative potential in in vitro ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical (DPPH) assays. Our results clearly show that PSB-KD-107 dilates blood vessels. This effect is related to its activation of GPR18 as it can be blocked by the GPR18 antagonist PSB-CB-92. Moreover, our finding confirms the presence of GPR18 in blood vessels. The mechanism of the vasorelaxant activity of PSB-KD-107 is mainly related to endothelial nitric oxide generation; however, we cannot exclude additional nitric oxide-independent mechanisms or a direct influence on K channels. PSB-KD-107 may affect blood pressure and heart function after a single administration; however, this effect was no longer observed after repeated administrations once daily for eight days. PSB-KD-107 does not affect platelet aggregation-an important feature considering the safety of its administration. PSB-KD-107 also shows a significant anti-oxidant effect and further studies of its antioxidant activity in vivo are justified.
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http://dx.doi.org/10.3390/ph14080799DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398562PMC
August 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

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

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

Structural modifications in the distal, regulatory region of histamine H receptor antagonists leading to the identification of a potent anti-obesity agent.

Eur J Med Chem 2021 Mar 24;213:113041. Epub 2020 Nov 24.

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

A series of 4-pyridylpiperazine derivatives with varying regulatory region substituents proved to be potent histamine H receptor (HR) ligands in the nanomolar concentration range. The most influential modification that affected the affinity toward the HR appeared by introducing electron-withdrawing moieties into the distal aromatic ring. In order to finally discuss the influence of the characteristic 4-pyridylpiperazine moiety on HR affinity, two Ciproxifan analogues 2 and 3 with a slight modification in their basic part were obtained. The replacement of piperazine in 3 with piperidine in compound 2, led to slightly reduced affinity towards the HR (K = 3.17 and 7.70 nM, respectively). In fact, 3 showed the highest antagonistic properties among all compounds in this series, hence affirming our previous assumptions, that the 4-pyridylpiperazine moiety is the key element for suitable interaction with the human histamine H receptor. While its structural replacement to piperidine is also tolerated for HR binding, the heteroaromatic 4-pyridyl moiety seems to be essential for proper ligand-receptor interaction. The putative protein-ligand interactions responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at the HR, as well as drug-like properties of ligands were evaluated using in vitro methods. Moreover, pharmacological in vivo test results of compound 9 (structural analogue of Abbott's A-331440) clearly indicate that it may affect the amount of calories consumed, thus act as an anorectic compound.
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http://dx.doi.org/10.1016/j.ejmech.2020.113041DOI Listing
March 2021

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

Antidepressant-like activity and safety profile evaluation of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione derivatives as 5-HT1A receptor partial agonists.

PLoS One 2020 7;15(8):e0237196. Epub 2020 Aug 7.

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

Current antidepressant therapy has several disadvantages related to the properties of antidepressants. Considering their unfavourable features, the process of searching for new antidepressant drugs with better safety and tolerability requires consistent efforts and many complementary studies. Serotonin 5-HT1A receptor is considered as an interesting target of antidepressant therapy. In the present study, the intrinsic activity at different signaling pathways coupled to serotonin 5-HT1A receptor, antidepressant-like and pharmacokinetic properties, and the safety profile of two novel imidazopurine-2,4-dione derivatives, namely compounds AZ-853 (8-(4-(4-(2-fluorophenyl)piperazin-1-yl)butyl)-1,3-dimethyl-1H- imidazo[2,1-f]purine-2,4(3H,8H)-dione) and AZ-861 (1,3-dimethyl-8-(4-(4-(3-(trifluoromethyl)phenyl)piperazin-1-yl)butyl)-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione), were studied in animal models through in vitro and in vivo experiments. We demonstrated that AZ-853 and AZ-861, which structurally differ by one substituent and its placement in the phenyl ring, showed varied functional, pharmacological, and pharmacokinetic properties as well as side effect profiles. AZ-861 exhibited stronger agonistic action in all functional assays. After acute and repeated administration in mice, both compounds showed antidepressant-like activity in the forced swim test, which was partially mediated by 5-HT1A receptor activation. AZ-853 showed a more potent antidepressant-like effect, presumably due to its better penetration into brain structures. Both compounds did not show anticholinergic properties, but after repeated administration, they induced weak sedation and lipid metabolism disturbances without affecting serum glucose level. The stronger α1-adrenolytic effect of AZ-853 is responsible for decreased systolic blood pressure, and in contrast to AZ-861, AZ-853 induced weight gain in mice. The interesting comparative pharmacological profiles of AZ-853 and AZ-861 encourage to conduct further experiments to fully understand their mechanisms and differences in action.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237196PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7413516PMC
October 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

Structural modifications and in vitro pharmacological evaluation of 4-pyridyl-piperazine derivatives as an active and selective histamine H receptor ligands.

Bioorg Chem 2019 10 20;91:103071. Epub 2019 Jun 20.

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

A novel series of 4-pyridylpiperazine derivatives with varying alkyl linker length and eastern part substituents proved to be potent histamine H receptor (hHR) ligands in the nanomolar concentration range. While paying attention to their alkyl linker length, derivatives with a six methylene linker tend to be more potent than their five methylene homologues. Moreover, in the case of both phenoxyacetyl- and phenoxypropionyl- derivatives, an eight methylene linkers possess lower activity than their seven methylene homologues. However, in global analysis of collected data on the influence of alkyl linker length, a three methylene homologues appeared to be of highest hHR affinity among all described 4-pyridylpiperazine derivatives from our group up to date. In the case of biphenyl and benzophenone derivatives, compounds with para- substituted second aromatic ring were of higher affinity than their meta analogues. Interestingly, benzophenone derivative 18 showed the highest affinity among all tested compounds (hHR K = 3.12 nM). The likely protein-ligand interactions, responsible for their high affinity were demonstrated using molecular modeling techniques. Furthermore, selectivity, intrinsic activity at HR, as well as drug-like properties of selected ligands were evaluated using in vitro methods.
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http://dx.doi.org/10.1016/j.bioorg.2019.103071DOI Listing
October 2019

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

Isolation of 1-(3',4'-Dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol from Grape Seed Extract and Evaluation of its Antioxidant and Antispasmodic Potential.

Molecules 2019 Jul 4;24(13). Epub 2019 Jul 4.

Planta Analytica LLC, New Milford, CT 06776, USA.

HPLC profiling of phenolics in grape seed extracts revealed a prominent peak of an unknown substance with concentrations up to 5.3%. Spectroscopic data allowed the identification of the compound as 1-(3',4'-dihydroxyphenyl)-3-(2″,4″,6″-trihydroxyphenyl)-propan-2-ol. is known to be produced from catechin and epicatechin through anaerobic bacteria from human, as well as the rat, intestines. It was hypothesized that the marc remaining after expression of juice from grapes became infested during storage, resulting in the production of . Because compound is infrequently found in nature and has never been found in grape seeds, its presence may be considered a marker of an unwanted anaerobic bacterial process occurring during production. The antioxidant potential of was determined by DPPH, ABTS, and FRAP (ferric reducing antioxidant power) assays and compared to the potential of the following compounds: phloroglucine, pyrogallol, gallic acid, catechin, and epicatechin. Furthermore, it was established that significantly reduced guinea pig ileum contraction induced by histamine.
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http://dx.doi.org/10.3390/molecules24132466DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6651082PMC
July 2019

Anti-Alzheimer's multitarget-directed ligands with serotonin 5-HT antagonist, butyrylcholinesterase inhibitory, and antioxidant activity.

Arch Pharm (Weinheim) 2019 Jul 4;352(7):e1900041. Epub 2019 Jun 4.

Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.

Serotonin 5-HT receptors, butyrylcholinesterase (BuChE) and oxidative stress are related to the pathophysiology of Alzheimer's disease. Inhibition of BuChE provides symptomatic treatment of the disease and the same effect was demonstrated for 5-HT antagonists in clinical trials. Oxidative stress is regarded as a major and primary factor contributing to the development of Alzheimer's disease; therefore, antioxidant agents may provide a disease-modifying effect. Combining BuChE inhibition, 5-HT antagonism, and antioxidant properties may result in multitarget-directed ligands providing cognition-enhancing properties with neuroprotective activity. On the basis of the screening of the library of 5-HT antagonists against BuChE, we selected two compounds and designed their structural modifications that could lead to improved BuChE inhibitory activity. We synthesized two series of compounds and tested their affinity and functional activity at 5-HT receptors, BuChE inhibitory activity and antioxidant properties. Compound 12 with K and K values against 5-HT receptors of 41.8 and 74 nM, respectively, an IC value of 5 µM against BuChE and antioxidant properties exceeding the activity of ascorbic acid is a promising lead structure for further development of anti-Alzheimer's agents.
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http://dx.doi.org/10.1002/ardp.201900041DOI Listing
July 2019

Characteristics of metabolic stability and the cell permeability of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione with antidepressant- and anxiolytic-like activities.

Chem Biol Drug Des 2019 04 4;93(4):511-521. Epub 2018 Dec 4.

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

A series of 2-pyrimidinyl-piperazinyl-alkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione has been synthesized in an attempt to discover a new class of psychotropic agents. Compounds were evaluated for their in vitro affinity for serotonin 5-HT , 5-HT , and phosphodiesterases PDE4 and PDE10. The most potent compound 2-pyrimidinyl-1-piperazinyl-butyl-imidazo[2,1-f]purine-2,4-dione (4b) behaved as strong and selective antagonist of 5-HT . Molecular modeling studies revealed differences in binding mode between compound 4b and buspirone, which might reflect variation of the ligands' affinity and potency in the 5-HT receptor. Compound 4b in silico models demonstrated drug-likeness properties and, contrary to buspirone, showed a metabolic stability in mouse liver microsomes system. Experimentally obtained value of apparent permeability coefficient P for 4b in parallel artificial permeability assay indicates the possibility of binding weakly to plasma proteins and high intestinal absorption fraction. Evaluation of the antidepressant- and anxiolytic-like activities of 4b revealed both activities at the same dose of 1.25 mg/kg and seemed to be specific. The antidepressant and/or anxiolytic properties of 4b may be related to its first-pass effect.
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http://dx.doi.org/10.1111/cbdd.13442DOI Listing
April 2019

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

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

Novel multi-target azinesulfonamides of cyclic amine derivatives as potential antipsychotics with pro-social and pro-cognitive effects.

Eur J Med Chem 2018 Feb 3;145:790-804. Epub 2018 Jan 3.

Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, 12 Smętna Street, 31-343 Kraków, Poland. Electronic address:

Currently used antipsychotics are characterized by multireceptor mode of action. While antagonism of dopamine D receptors is responsible for the alleviation of "positive" symptoms of schizophrenia and the effects at other, particularly serotonergic receptors are necessary for their additional therapeutic effects, there is no consensus regarding an "ideal" target engagement. Here, a detailed SAR analysis in a series of 45 novel azinesulfonamides of cyclic amine derivatives, involving the aryl-piperazine/piperidine pharmacophore, central alicyclic amine and azinesulfonamide groups has led to the selection of (S)-4-((2-(2-(4-(benzo[b]thiophen-4-yl)piperazin-1-yl)ethyl)pyrrolidin-1-yl)sulfonyl)isoquinoline (62). The polypharmacology profile of 62, characterized by partial 5-HTR agonism, 5-HT/5-HT/D/DR antagonism, and blockade of SERT, reduced the "positive"-like, and "negative"-like symptoms of psychoses. Compound 62 produced no catalepsy, demonstrated a low hyperprolactinemia liability and displayed pro-cognitive effects in the novel object recognition task and attentional set-shifting test. While association of in vitro features with the promising in vivo profile of 62 is still not fully established, its clinical efficacy should be verified in further stages of development.
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http://dx.doi.org/10.1016/j.ejmech.2018.01.002DOI Listing
February 2018

Metabolic benefits of 1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one: a non-selective α-adrenoceptor antagonist.

J Endocrinol Invest 2018 May 7;41(5):609-619. Epub 2017 Nov 7.

Chair of Pharmaceutical Chemistry, Department of Physicochemical Drug Analysis, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna 9, 30-688, Kraków, Poland.

Purpose: Previous studies have shown that several components of the metabolic syndrome, such as hypertension, obesity or imbalanced lipid and carbohydrate homeostasis, are associated with the sympathetic nervous system overactivity. Therefore, the inhibition of the adrenergic nervous system seems to be a reasonable and appropriate therapeutic approach for the treatment of metabolic disturbances. It has been suggested that non-selective adrenoceptor antagonists could be particularly beneficial, since α-adrenoceptor antagonists can improve disrupted lipid and carbohydrate profiles, while the inhibition of the α-adrenoceptor may contribute to body weight reduction. The aim of the present study was to investigate the metabolic benefits deriving from administration of a non-selective α-adrenoceptor antagonist from the group of pyrrolidin-2-one derivatives. The aim of the present study was to investigate the potential metabolic benefits deriving from chronic administration of a non-selective α-adrenoceptor antagonist, from the group of pyrrolidin-2-one derivatives.

Methods: The α- and α-adrenoreceptor affinities of the tested compound-1-(3-(4-(o-tolyl)piperazin-1-yl)propyl)pyrrolidin-2-one had been investigated previously by means of the radioligand binding assay. In the present study, we extended the pharmacological profile characteristics of the selected molecule by additional intrinistic activity assays. Next, we investigated the influence of the tested compound on body weight, hyperglycemia, hypertriglyceridemia, blood pressure in the animal model of obesity induced by a high-fat diet, and additionally we measured the spontaneous activity and body temperature.

Results: The intrinistic activity studies revealed that the tested compound is a potent, non-selective antagonist of α and α-adrenoceptors. After the chronic administration of the tested compound, we observed reduced level of triglycerides and glucose in the rat plasma. Interestingly, the tested did not reduce the body weight and did not influence the blood pressure in normotensive animals. Additionally, the administration of the tested compound did not change the animals' spontaneous activity and body temperature.

Conclusion: Non-selective α-adrenoceptor antagonist seems to carry potential benefits in the improvement of the reduction of elevated glucose and triglyceride level. The lack of influence on blood pressure suggests that compounds with such a pharmacological profile may be particulary beneficial for the patients with disturbed lipid and carbohydrate profile, who do not suffer from hypertension. These results are particulary valuable, since currently there are no safe α-adrenoceptor antagonist drugs available in clinical use with the ability to modulate hyperglycemia that would not affect blood pressure.
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http://dx.doi.org/10.1007/s40618-017-0779-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5902538PMC
May 2018

The effect of NaCl on the level of reduced sulfur compounds in rat liver. Implications for blood pressure increase.

Postepy Hig Med Dosw (Online) 2017 Jul 7;71(0):564-576. Epub 2017 Jul 7.

Chair of Medical Biochemistry, Jagiellonian University Medical College, Kraków, Poland.

Background: It is commonly known that excessive salt intake is a risk factor of hypertension. Currently, there is an increasing interest in reduced reactive sulfur species (RSS), mainly H2S and sulfane sulfur (SS) as new gasotransmitters showing vasorelaxant properties. The aim of the present study was to determine the effect of repeated administration of low sodium chloride dose included in physiological saline on blood pressure, on the level of RSS and activity of enzymes involved in their biosynthesis in the rat.

Methods: Two separate experiments were carried out on male Wistar rats: one with intravenous injections of saline and the second one with intraperitoneal saline injections. Blood pressure was measured during the experiment. The level of RSS and other biochemical assays were conducted in the rat liver, because of an intense cysteine metabolism to RSS in this organ.

Results: Intravenous administration of saline induced a significant increase in systolic blood pressure while intraperitoneal injections showed only a tendency towards increasing blood pressure. The RSS (H2S and SS) level as well as the activity of the main enzyme responsible for their production in the liver of animals after iv saline injections were decreased. Animals injected with physiological saline by ip route did not reveal any statistically significant differences in SS, H2S, and activities of sulfurtransferases, although a tendency to decrease in the RSS was observed.

Conclusions: The repeated iv saline injection induced a slight hypertension accompanied by disturbances in anaerobic cysteine metabolism in the rat liver.
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http://dx.doi.org/10.5604/01.3001.0010.3837DOI Listing
July 2017

INACTIVATION OF ALDEHYDE DEHYDROGENASE BY NITROGLYCERIN IN THE PRESENCE AND ABSENCE OF LIPOIC ACID AND DIHYDROLIPOIC ACID. IMPLICATIONS FOR THE PROBLEM OF DIFFERENTIAL EFFECTS OF LIPOIC ACID IN VITRO AND IN VIVO.

Acta Pol Pharm 2016 Nov;73(6):1531-1538

Lipoic acid (LA-(SS), LA) and its reduced form - dihydrolipoic acid DHLA-(SH)2, DHLA) are synthesized mainly in the mammalian liver. In this study, we investigated in viti the inactivation of yeast aldehyde dehydrogenase (ALDH) by nitroglycerin (GTN) in the presence and absence of LA and DHLA. In vivo studies were performed to answer the question whether LA administered jointly with GTN for 8 days will affect the ALDH activity in the rat liver. The results indicated that in vito both LA and DHLA restored and protected ALDH activity against GTN-induced inactivation, while treatment of rats with LA and GTN in combination did not provide any protection against GTN-induced ALDH inhibition. In summary, the obtained results seem to confirm earlier reports indicating the differential effects of LA in vitio and in vivo.
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November 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

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

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

Pyrrolidin-2-one derivatives may reduce body weight in rats with diet-induced obesity.

Eur J Pharmacol 2016 Apr 17;776:146-55. Epub 2016 Feb 17.

Department of Pharmacological Screening, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, 30-688 Kraków, Poland.

Unlabelled: Obesity affects an increasing number of individuals in the human population and significant importance is attached to research leading to the discovery of drug which would effectively reduce weight. The search for new drugs with anorectic activity and acting within the adrenergic system has attracted the interest of researchers. This study concerns the experimental effects on body weight of α2-adrenoceptor antagonists from the group of pyrrolidin-2-one derivatives in rats with diet-induced obesity.

Methods: The intrinsic activity of the test compounds at the α-adrenoreceptors was tested. Obesity in rats was obtained by the use of fatty diet and then the influence of the test compounds on body weight, food and water intakes, lipid and glucose profiles and glycerol and cortisol levels were determinated. The effects of the compounds on locomotor activity, body temperature, blood pressure and heart rate were tested.

Results: One of the test compounds (1-(3-(4-phenylpiperazin-1-yl)propyl)pyrrolidin-2-one) reduces the animal's body weight and the amount of peritoneal adipose tissue during chronic administration, at the same time it does not cause significant adverse effects on the cardiovascular system. This compound decreases temperature and elevates glycerol levels and does not change the locomotor activity and cortisol level at anti-obese dose.

Conclusions: Some derivatives of pyrrolidin-2-one that act as antagonists of the α2-adrenoreceptor may reduce body weight. Reducing body weight for 1-(3-(4-phenylpiperazin-1-yl)propyl)pyrrolidin-2-one can be associated with decrease in food intake, body fat reduction, reduction of blood glucose, and increased thermogenesis and lipolysis. This effect cannot be the result of changes in spontaneous activity or stress.
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http://dx.doi.org/10.1016/j.ejphar.2016.02.047DOI Listing
April 2016

Synthesis and Pharmacological Activity of a New Series of 1-(1H-Indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol Analogs.

Arch Pharm (Weinheim) 2016 Mar 8;349(3):211-23. Epub 2016 Feb 8.

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

β-Adrenergic receptor antagonists are important therapeutics for the treatment of cardiovascular disorders. In the group of β-blockers, much attention is being paid to the third-generation drugs that possess important ancillary properties besides inhibiting β-adrenoceptors. Vasodilating activity of these drugs is produced through different mechanisms, such as nitric oxide (NO) release, β2 -agonistic action, α1 -blockade, antioxidant action, and Ca(2+) entry blockade. Here, a study on evaluation of the cardiovascular activity of five new compounds is presented. Compound 3a is a methyl and four of the tested compounds (3b-e) are dimethoxy derivatives of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol. The obtained results confirmed that the methyl and dimethoxy derivatives of 1-(1H-indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol and their enantiomers possess α1 - and β1 -adrenolytic activities and that the antiarrhythmic and hypotensive effects of the tested compounds are related to their adrenolytic properties.
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http://dx.doi.org/10.1002/ardp.201500234DOI Listing
March 2016

Antidepressant-like activity of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and evidence for the involvement of serotonin receptor subtypes in their mechanism of action.

Pharmacol Biochem Behav 2016 Feb 2;141:28-41. Epub 2015 Dec 2.

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

Since serotonin (5-HT) is strongly involved in the etiology and pathophysiology of depression, the development of new antidepressants is still based on the serotonergic system. The complexity of serotonergic system provides an opportunity for the development of compounds with multiple and complementary mechanism of action. This study describes serotonin receptor profile, functional characterization, and pharmacological in vivo evaluation of new aroxyalkyl derivatives of 2-methoxyphenylpiperazine. The obtained results allowed for the identification of compound 3, (1-[3-(2,6-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride), a partial 5-HT1A receptor agonist, and 5-HT2A receptor antagonist, with high affinity toward 5-HT7 receptors, showing antidepressant- and anxiolytic-like properties. Moreover, 5-HT1A receptor activation is crucial for the antidepressant-like activity of compound 3. The rest of the compounds (except compounds 1 and 9) showed antidepressant but not anxiolytic-like properties, which did not result from 5-HT1A receptors activation. Furthermore, the compounds are 5-HT1A and weak 5-HT3 receptors antagonists, and some of them 5-HT2A antagonists. Moreover, none of the studied compounds impaired motor coordination at antidepressant-like doses. Since the studied compounds exhibited activity in behavioral assays and interacted with various receptors, the results of our experiments are very promising and require further studies.
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http://dx.doi.org/10.1016/j.pbb.2015.11.013DOI Listing
February 2016

Antiarrhythmic and α-Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin-2-one.

Arch Pharm (Weinheim) 2015 Dec 2;348(12):861-7. Epub 2015 Nov 2.

Department of Physicochemical Drug Analysis, Chair of Pharmaceutical Chemistry, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland.

In an effort to develop α-adrenoceptor antagonists with antiarrhythmic activity, we designed a series of pyrrolidin-2-one derivatives. The α1- and α2-adrenorecepor affinities of the new pyrrolidin-2-one derivatives were determined using a radioligand binding assay. The most active compound was then tested in vitro for intrinsic activity toward α(1A)- and α(1B)-adrenoceptors and in vitro for antiarrhythmic activity in epinephrine-induced arrhythmia in rats. The highest affinity for the α1-adrenoceptor (pK(i) = 7.01) was displayed by 1-{4-[4-(2-methoxy-5-chlorophenyl)-piperazin-1-yl]-methyl}-pyrrolidin-2-one (9). 1-[4-(2-Fluorophenyl)-piperazin-1-yl]-methyl-pyrrolidin-2-one (7) showed the highest affinity toward the α2-adrenoceptor (pK(i) = 6.52). Intrinsic activity studies of compound 9 showed that this compound is an antagonist of both α(1A)- (EC50 = 0.5 nM) and α(1B)- (EC50 = 51.0 nM) adrenoceptors. Compound 9 displayed antiarrhythmic activity in rats (ED50 = 5.0 mg/kg (3.13-7.99)). New derivatives of pyrrolidin-2-one with α1 -adrenoceptor affinity were identified. We propose that the antiarrhythmic activity of compound 9 is related to its antagonism of α(1A)- and α(1B)-adrenoceptors.
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http://dx.doi.org/10.1002/ardp.201500180DOI Listing
December 2015

A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity.

PLoS One 2015 27;10(10):e0141327. Epub 2015 Oct 27.

Department of Pharmacodynamics, Jagiellonian University, Collegium Medicum, 9 Medyczna Street, PL 30-688 Kraków, Poland.

The search for drugs with anorectic activity, acting within the adrenergic system has attracted the interest of researchers. Partial α2-adrenoceptor agonists might offer the potential for effective and safe treatment of obesity. We compared the effectiveness and safety of α2-adrenoceptor ligands in reducing body mass. We also analyzed if antagonist and partial agonists of α2-adrenoceptor--yohimbine and guanfacine--act similarly, and determined which course of action is connected with anorectic activity. We tested intrinsic activity and effect on the lipolysis of these compounds in cell cultures, evaluated their effect on meal size, body weight in Wistar rats with high-fat diet-induced obesity, and determined their effect on blood pressure, heart rate, lipid profile, spontaneous locomotor activity, core temperature and glucose, as well as glycerol and cortisol levels. Both guanfacine and yohimbine showed anorectic activity. Guanfacine was much more effective than yohimbine. Both significantly reduced the amount of intraperitoneal adipose tissue and had a beneficial effect on lipid profiles. Decreased response of α2A-adrenoceptors and partial stimulation of α2B-receptors seem to be responsible for the anorectic action of guanfacine. The stimulation of α1-adrenoceptors by guanfacine is responsible for cardiovascular side effects but may also be linked with improved anorexic effect. α1-adrenoceptor blockade is connected with the side effects of yohimbine, but it is also associated with the improvement of lipid profiles. Guanfacine has been approved by the Food and Drug Administration (FDA) to treat hypertension and conduct disorder, but as it reduces body weight, it is worth examining its effectiveness and safety in models of obesity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0141327PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4624629PMC
June 2016

Antiarrhythmic activity in occlusion-reperfusion model of 1-(1H-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy)ethyl]amino} propan-2-ol and its enantiomers.

Clin Exp Pharmacol Physiol 2016 Jan;43(1):81-7

Department of Pharmacological Screening, Jagiellonian University Medical College, Kraków, Poland.

Acute myocardial infarction (AMI) is a leading cause of mortality and morbidity worldwide, especially in developed countries. The most serious problem after myocardial infarction is reperfusion injury that manifests as functional impairment, arrhythmia, and accelerated progression of cell death in certain critically injured myocytes. Subsequently the infarcted myocardium develops features of necrosis and reactive inflammation. To reduce lethal reperfusion injury in patient with AMI antioxidants, anti-inflammatory agents, adenosine, opioids, metabolic modulators (glucose, insulin, and potassium, nicorandil and agents which reduce intracellular Ca(2+) overload and inhibit Na(+)-H(+) exchange) are used. In this study a novel compound (compound 9) 1-(1 h-indol-4-yloxy)-3-{[2-(2-methoxyphenoxy) ethyl]amino}propan-2-ol and its enantiomers are examined in arrhythmia associated with coronary artery occlusion and reperfusion in a rat model. Antioxidant properties are also determined for test compounds using the malondialdehyde (MDA) lipid peroxidation and ferric reducing antioxidant power (FRAP) tests. In summary, the tested compounds, especially the S enantiomer has a strong antiarrhythmic activity in a model of occlusion and reperfusion of the left coronary artery which is probably related to their adrenolytic action. In contrast to carvedilol, none of the test compound reduced the lipid peroxidation but increased ferric reducing antioxidant power. In the antioxidant effect, there was no difference between the optical forms of compound 9.
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http://dx.doi.org/10.1111/1440-1681.12491DOI Listing
January 2016

Synthesis and Analgesic Activity of Annelated Xanthine Derivatives in Experimental Models in Rodents.

Arch Pharm (Weinheim) 2015 Oct 6;348(10):704-14. Epub 2015 Aug 6.

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

A series of annelated derivatives of xanthine were synthesized and assayed as potential analgesic agents. All synthesized xanthine derivatives were tested in the writhing test and hot-plate test. The pharmacological assays demonstrated that all the compounds prepared, without exception, displayed a significant activity in the mouse writhing assay. The analgesic action of the most active compounds, expressed as ED50 was found to be 1.4-4.3 times more potent than that of acetylsalicylic acid used as the reference compound. However, only some of the compounds demonstrated analgesic activity in the hot-plate test. The analgesic effect of some compounds is probably related to their agonistic, antagonistic, or partial agonistic activity at the adenosine receptors.
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http://dx.doi.org/10.1002/ardp.201500169DOI Listing
October 2015
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