27 results on '"Barbara Mordyl"'
Search Results
2. Vanadium Complexes with Thioanilide Derivatives of Amino Acids: Inhibition of Human Phosphatases and Specificity in Various Cell Models of Metabolic Disturbances
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Grzegorz Kazek, Monika Głuch-Lutwin, Barbara Mordyl, Monika Kubacka, Anna Jurowska, Dariusz Cież, Bartosz Trzewik, Janusz Szklarzewicz, and Monika A. Papież
- Abstract
In the text, the synthesis and characteristics of the novel ONS-type vanadium(V) complexes with thioanilide derivatives of amino acids are described. They have shown inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1 and SHP2) in the submicromolar range, as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxovanadium(IV)(BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070, also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as Schiff base ligand components, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models in general. Moreover, the majority of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathways in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all of the above models, also including glucose utilization in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion section explicates the results within the wider scope of the knowledge about vanadium complexes.
- Published
- 2023
3. Vanadium Complexes with Thioanilidine Derivatives of Aminoacids: Inhibition of Human Phosphatases and Cell-Type Specificity in Various Models of Metabolic Disturbances
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Grzegorz Kazek, Monika Głuch-Lutwin, Barbara Mordyl, Monika Kubacka, Anna Jurowska, Dariusz Cież, Bartosz Trzewik, Janusz Szklarzewicz, and Monika A. Papież
- Abstract
The synthesis and characteristics of the novel ONS-type vanadium(V) complexes with thioanilidine derivatives of aminoacids have been described. They showed inhibition of human protein tyrosine phosphatases (PTP1B, LAR, SHP1 and SHP2) in the submicromolar range and as well as inhibition of non-tyrosine phosphatases (CDC25A and PPA2) similar to bis(maltolato)oxovanadium(IV)(BMOV). The ONS complexes increased [14C]-deoxy-D-glucose transport into C2C12 myocytes, and one of them, VC070 also enhanced this transport in 3T3-L1 adipocytes. These complexes inhibited gluconeogenesis in hepatocytes HepG2, but none of them decreased lipid accumulation in the non-alcoholic fatty liver disease model using the same cells. Compared to the tested ONO-type vanadium complexes with 5-bromosalicylaldehyde and substituted benzhydrazides as components of Schiff base ligand, the ONS complexes revealed stronger inhibition of protein tyrosine phosphatases, but the ONO complexes showed greater activity in the cell models, in general. Moreover, the most of the active complexes from both groups showed better effects than VOSO4 and BMOV. Complexes from both groups activated AKT and ERK signaling pathway in hepatocytes to a comparable extent. One of the ONO complexes, VC068, showed activity in all above models, including also glucose utilization in the myocytes and glucose transport in insulin-resistant hepatocytes. The discussion has put forward explications for the results within the wider scope of the knowledge about vanadium complexes.
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- 2023
4. Hybrid molecules combining GABA-A and serotonin 5-HT
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Monika, Marcinkowska, Barbara, Mordyl, Nikola, Fajkis-Zajaczkowska, Agata, Siwek, Tadeusz, Karcz, Alicja, Gawalska, Adam, Bucki, Paweł, Żmudzki, Anna, Partyka, Magdalena, Jastrzębska-Więsek, Bartosz, Pomierny, Maria, Walczak, Magdalena, Smolik, Karolina, Pytka, Kamil, Mika, Magdalena, Kotańska, and Marcin, Kolaczkowski
- Abstract
There is clear evidence that the presence of inflammatory factors and impaired GABA-ergic neurotransmission in depressed patients is associated with poor clinical outcome. We designed hybrid molecules, bearing the GABA molecule assembled with chemical fragments that interact with the serotonin 5-HT
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- 2022
5. Characterization and antidiabetic activity of salicylhydrazone Schiff base vanadium(IV) and (V) complexes
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Maciej Hodorowicz, Elżbieta Menaszek, Barbara Mordyl, Janusz Szklarzewicz, Jacek Sapa, Anna Jurowska, and Grzegorz Kazek
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Schiff base ,010405 organic chemistry ,Stereochemistry ,Phosphatase ,Metals and Alloys ,Vanadium ,chemistry.chemical_element ,Biological activity ,010403 inorganic & nuclear chemistry ,Hydrazide ,01 natural sciences ,0104 chemical sciences ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,Materials Chemistry ,Tyrosine ,Cytotoxicity ,Organometallic chemistry - Abstract
Twenty-four oxidovanadium(IV,V) complexes with tridentate Schiff base ligands based on 5-nitrosalicylaldehyde, 5-methoxysalicylaldehyde, or 5-sulfosalicylaldehyde and respective hydrazide were isolated, and characterized using physicochemical and spectroscopic methods. Three of them were structurally characterized by single-crystal X-ray structure determination. The biological activity studies included inhibition of human tyrosine phosphatases, studies on myocyte C2C12, adipocyte 3T3-L1, and human hepatocyte HepG2 cell lines, glucose uptake in myocytes and adipocytes, and cytotoxicity tests. The complexes that were unstable in solutions showed biological activity typical of other V(IV) complexes, while the stable one showed much higher, ligand-dependent, activity.
- Published
- 2020
6. Modulation of the MOP Receptor (μ Opioid Receptor) by Imidazo[1,2
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Dominik, Straszak, Agata, Siwek, Monika, Głuch-Lutwin, Barbara, Mordyl, Marcin, Kołaczkowski, Aldona, Pietrzak, Mansur, Rahnama-Hezavah, Bartłomiej, Drop, and Dariusz, Matosiuk
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Analgesics, Opioid ,Cricetulus ,Morphine ,Cricetinae ,Imidazoles ,Receptors, Opioid, mu ,Animals ,Humans ,Enkephalin, Ala(2)-MePhe(4)-Gly(5) - Abstract
The μ-opioid receptors belong to the family of G protein-coupled receptors (GPCRs), and their activation triggers a cascade of intracellular relays with the final effect of analgesia. Classical agonists of this receptor, such as morphine, are the main targets in the treatment of both acute and chronic pain. However, the dangerous side effects, such as respiratory depression or addiction, significantly limit their widespread use. The allosteric centers of the receptors exhibit large structural diversity within particular types and even subtypes. Currently, a considerable interest is aroused by the modulation of μ-opioid receptors. The application of such a technique may result in a reduction in the dose or even discontinuation of classical opiates, thus eliminating the side effects typical of this class of drugs. Our aim is to obtain a series of 1-aryl-5,6(1
- Published
- 2022
7. Design, synthesis, and behavioral evaluation of dual-acting compounds as phosphodiesterase type 10A (PDE10A) inhibitors and serotonin ligands targeting neuropsychiatric symptoms in dementia
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Agnieszka Zagórska, Adam Bucki, Anna Partyka, Magdalena Jastrzębska-Więsek, Agata Siwek, Monika Głuch-Lutwin, Barbara Mordyl, Anna Jaromin, Maria Walczak, Anna Wesołowska, and Marcin Kołaczkowski
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Pharmacology ,Mice ,Serotonin ,Phosphoric Diester Hydrolases ,Organic Chemistry ,Drug Discovery ,Animals ,Humans ,Dementia ,General Medicine ,Ligands ,Antipsychotic Agents - Abstract
Neuropsychiatric symptoms (NPS), such as psychosis, depression and anxiety are frequently observed among patients with dementia. NPS is treated by off-label psychotropic medications that are only modestly effective in dementia patients, with a high risk of adverse events and cognitive decline. Considering the above, there is an unmet need for a well-tolerated and effective therapy of NPS in dementia. We designed and synthesized a library of dual-acting compounds as phosphodiesterase type-10A inhibitors and serotonin 5-HT
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- 2022
8. New Dual Small Molecules for Alzheimer’s Disease Therapy Combining Histamine H3 Receptor (H3R) Antagonism and Calcium Channels Blockade with Additional Cholinesterase Inhibition
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Javier Egea, Daniel Diez-Iriepa, Barbara Mordyl, Alejandra Palomino-Antolín, Rim Malek, Lhassane Ismaili, Tereza Kobrlova, Justyna Godyń, Ondrej Soukup, José Marco-Contelles, Agata Siwek, Fakher Chabchoub, Ignacio Moraleda, Cristóbal de los Ríos, Dawid Panek, Céline Demougeot, Perle Totoson, Katarzyna Kieć-Kononowicz, Isabel Iriepa, Monika Głuch-Lutwin, Barbara Malawska, and Raquel L Arribas
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0303 health sciences ,biology ,Lipopolysaccharide ,Voltage-dependent calcium channel ,Pharmacology ,01 natural sciences ,0104 chemical sciences ,Blockade ,010404 medicinal & biomolecular chemistry ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,biology.protein ,Molecular Medicine ,Histamine H3 receptor ,Receptor ,Antagonism ,IC50 ,030304 developmental biology ,Cholinesterase - Abstract
New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good Ca2+ channels blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (Ki = 565 ± 62 nM), a moderate but selective hBuChE inhibition (IC50 = 7.83 ± 0.10 μM), strong antioxidant power (3.6 TE), and ability to restore cognitive impairment induced by lipopolysaccharide.
- Published
- 2019
9. Antipsychotic- and Anxiolytic-like Properties of a Multimodal Compound JJGW08 in Rodents
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Elżbieta Żmudzka, Klaudia Lustyk, Monika Głuch-Lutwin, Barbara Mordyl, Alicja Zakrzewska-Sito, Paweł Mierzejewski, Jolanta Jaśkowska, Marcin Kołaczkowski, Jacek Sapa, and Karolina Pytka
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Inorganic Chemistry ,Organic Chemistry ,General Medicine ,Physical and Theoretical Chemistry ,antipsychotic-like activity ,anxiolytic-like effect ,D2 receptor antagonist ,5-HT1A receptor antagonist ,arylpiperazine derivative of salicylamide ,Molecular Biology ,Spectroscopy ,Catalysis ,Computer Science Applications - Abstract
Schizophrenia is a chronic mental illness, which remains difficult to treat. A high resistance to the available therapies, their insufficient efficacy, and numerous side effects are the reasons why there is an urgent need to develop new antipsychotics. This study aimed to assess the antipsychotic-like effects of JJGW08, a novel arylpiperazine alkyl derivative of salicylamide, in rodents. First, considering the JJGW08 receptor profile, we investigated the compound’s intrinsic activity towards dopamine D2 and serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors using functional assays. Next, we assessed the effect of JJGW08 on MK-801- and amphetamine-induced hyperlocomotion, its risk of inducing catalepsy and impairing motor coordination, as well as the anxiolytic-like effects in the four-plate and marble burying tests in mice. Finally, we investigated the antipsychotic-like properties of JJGW08 in rats using MK-801-induced hyperlocomotion and prepulse inhibition tests. We found that JJGW08 showed antagonistic properties at dopamine D2 and serotonin 5-HT1A, 5-HT2A, and 5-HT7 receptors. However, the effect on the 5-HT2A and 5-HT7 receptors was very weak. Moreover, the tested compound showed an antipsychotic-like effect in MK-801- and amphetamine-induced hyperlocomotion but not in a prepulse inhibition test in rats. Notably, JJGW08 demonstrated anxiolytic-like properties in both behavioral tests. Importantly, the compound did not induce catalepsy or motor coordination impairment in mice at antipsychotic-like doses. Our study suggests it is worth searching for new potential antipsychotics among arylpiperazine alkyl derivatives of salicylamide.
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- 2022
10. The Phenoxyalkyltriazine Antagonists for 5-HT
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Sylwia, Sudoł, Agnieszka, Cios, Magdalena, Jastrzębska-Więsek, Ewelina, Honkisz-Orzechowska, Barbara, Mordyl, Natalia, Wilczyńska-Zawal, Grzegorz, Satała, Katarzyna, Kucwaj-Brysz, Anna, Partyka, Gniewomir, Latacz, Agnieszka, Olejarz-Maciej, Anna, Wesołowska, and Jadwiga, Handzlik
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Male ,Molecular Structure ,Triazines ,Article ,Rats ,5-HT6 ligands ,ADME-Tox parameters ,procognitive effects ,Structure-Activity Relationship ,Receptors, Serotonin ,1,3,5-triazine ,Animals ,Humans ,Dementia ,Serotonin Antagonists ,Caco-2 Cells ,Rats, Wistar ,Cognition Disorders ,Alzheimer’s disease - Abstract
Among the serotonin receptors, one of the most recently discovered 5-HT6 subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT6 receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT6 receptor. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT6 receptor target.
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- 2021
11. Development and crystallography-aided SAR studies of multifunctional BuChE inhibitors and 5-HT
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Tomasz, Wichur, Justyna, Godyń, Izabella, Góral, Gniewomir, Latacz, Adam, Bucki, Agata, Siwek, Monika, Głuch-Lutwin, Barbara, Mordyl, Joanna, Śniecikowska, Maria, Walczak, Damijan, Knez, Marko, Jukič, Kinga, Sałat, Stanislav, Gobec, Marcin, Kołaczkowski, Barbara, Malawska, Xavier, Brazzolotto, and Anna, Więckowska
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Male ,Models, Molecular ,Amyloid beta-Peptides ,Dose-Response Relationship, Drug ,Molecular Structure ,Cell Survival ,Hep G2 Cells ,Crystallography, X-Ray ,Mice ,Protein Aggregates ,Structure-Activity Relationship ,Neuroprotective Agents ,Drug Development ,Alzheimer Disease ,Butyrylcholinesterase ,Receptors, Serotonin ,Electrophorus ,Animals ,Humans ,Cholinesterase Inhibitors ,Horses - Abstract
The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and a challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins and processes involved in the development of the disease: BuChE, 5-HT
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- 2021
12. An exit beyond the pharmacophore model for 5-HT
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Katarzyna, Kucwaj-Brysz, Wesam, Ali, Rafał, Kurczab, Sylwia, Sudoł-Tałaj, Natalia, Wilczyńska-Zawal, Magdalena, Jastrzębska-Więsek, Grzegorz, Satała, Barbara, Mordyl, Ewa, Żesławska, Agnieszka-Olejarz-Maciej, Kinga, Czarnota, Gniewomir, Latacz, Anna, Partyka, Anna, Wesołowska, Wojciech, Nitek, and Jadwiga, Handzlik
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Serotonin ,Molecular Structure ,Triazines ,Receptors, Serotonin ,Animals ,Serotonin Antagonists ,Rats - Abstract
This research allowed us to find the first highly potent 5-HT
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- 2021
13. V(III) and V(IV) Schiff base complexes as potential insulin-mimetic compounds – Comparison, characterization and biological activity
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Anna Jasińska, Janusz Szklarzewicz, Anna Jurowska, Maciej Hodorowicz, Grzegorz Kazek, Barbara Mordyl, and Monika Głuch-Lutwin
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Inorganic Chemistry ,Materials Chemistry ,Physical and Theoretical Chemistry - Published
- 2022
14. Chlorine substituents and linker topology as factors of 5-HT
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Sylwia, Sudoł, Katarzyna, Kucwaj-Brysz, Rafał, Kurczab, Natalia, Wilczyńska, Magdalena, Jastrzębska-Więsek, Grzegorz, Satała, Gniewomir, Latacz, Monika, Głuch-Lutwin, Barbara, Mordyl, Ewa, Żesławska, Wojciech, Nitek, Anna, Partyka, Kamila, Buzun, Agata, Doroz-Płonka, Anna, Wesołowska, Anna, Bielawska, and Jadwiga, Handzlik
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Molecular Docking Simulation ,Structure-Activity Relationship ,Cognition ,Protein Conformation ,Triazines ,Receptors, Serotonin ,Animals ,Chlorine ,Safety ,Rats - Abstract
In the light of recent lines of evidence, 5-HT
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- 2020
15. New Dual Small Molecules for Alzheimer's Disease Therapy Combining Histamine H
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Rim, Malek, Raquel L, Arribas, Alejandra, Palomino-Antolin, Perle, Totoson, Celine, Demougeot, Tereza, Kobrlova, Ondrej, Soukup, Isabel, Iriepa, Ignacio, Moraleda, Daniel, Diez-Iriepa, Justyna, Godyń, Dawid, Panek, Barbara, Malawska, Monika, Głuch-Lutwin, Barbara, Mordyl, Agata, Siwek, Fakher, Chabchoub, José, Marco-Contelles, Katarzyna, Kiec-Kononowicz, Javier, Egea, Cristóbal, de Los Ríos, and Lhassane, Ismaili
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Small Molecule Libraries ,Memory Disorders ,Mice ,Neuroblastoma ,Neuroprotective Agents ,Alzheimer Disease ,Vasodilator Agents ,Tumor Cells, Cultured ,Animals ,Humans ,Receptors, Histamine H3 ,Cholinesterase Inhibitors ,Calcium Channel Blockers - Abstract
New tritarget small molecules combining Ca
- Published
- 2019
16. 6-Acetyl-5-hydroxy-4,7-dimethylcoumarin derivatives: Design, synthesis, modeling studies, 5-HT
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Kinga, Ostrowska, Anna, Leśniak, Urszula, Karczyńska, Paulina, Jeleniewicz, Monika, Głuch-Lutwin, Barbara, Mordyl, Agata, Siwek, Bartosz, Trzaskowski, Mariusz, Sacharczuk, and Magdalena, Bujalska-Zadrożny
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Male ,Mice, Inbred BALB C ,Receptors, Dopamine D2 ,Acetylation ,CHO Cells ,Serotonin 5-HT1 Receptor Antagonists ,Methylation ,Molecular Docking Simulation ,Cricetulus ,Coumarins ,Drug Design ,Drug Discovery ,Receptor, Serotonin, 5-HT1A ,Animals ,Humans ,Receptor, Serotonin, 5-HT2A ,Piperazine - Abstract
Molecular docking studies using appropriate 5-HT
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- 2019
17. Molecular mechanism of action and safety of 5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione - a novel anticonvulsant drug candidate
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Adam Tomczykowski, Agata Siwek, Jarogniew J. Łuszczki, Tadeusz Karcz, Krzysztof Jóźwiak, Barbara Mordyl, Anna Gryboś, Karolina Pająk, Gabriel Nowak, Tomasz Plech, Monika Głuch-Lutwin, Monika Wujec, Barbara Kaproń, and Agata Paneth
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0301 basic medicine ,Patch-Clamp Techniques ,medicine.medical_treatment ,Sodium channels ,Voltage-Gated Sodium Channels ,Pharmacology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Seizures ,medicine ,Animals ,Humans ,Patch clamp ,[3H]-batrachotoxin ,Receptor ,Acetylcholine receptor ,Electroshock ,cell viability assays ,GABAA receptor ,Chemistry ,Sodium channel ,Thiones ,Hep G2 Cells ,General Medicine ,patch-clamp ,Triazoles ,Disease Models, Animal ,030104 developmental biology ,Nicotinic agonist ,Anticonvulsant ,Hepatic stellate cell ,Anticonvulsants ,030217 neurology & neurosurgery ,Research Paper - Abstract
Previously, it was found that 5-(3-chlorophenyl)-4-hexyl-2,4-dihydro-3H-1,2,4-triazole-3-thione (TP-315) effectively protects mice from maximal electroshock-induced seizures. The aim of this study was to determine possible interactions between TP-315 and different molecular targets, i.e. GABAA receptors, voltage-gated sodium channels, and human neuronal α7 and α4β2 nicotinic acetylcholine receptors. The influence of TP-315 on the viability of human hepatic HepG2 cells was also established using PrestoBlue and ToxiLight assays. It was found that the anticonvulsant activity of TP-315 results (at least partially) from its influence on voltage-gated sodium channels (VGSCs). Moreover, the title compound slightly affected the viability of human hepatic cells.
- Published
- 2017
18. Synthesis and computer-aided SAR studies for derivatives of phenoxyalkyl-1,3,5-triazine as the new potent ligands for serotonin receptors 5-HT
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Wesam, Ali, Małgorzata, Więcek, Dorota, Łażewska, Rafał, Kurczab, Magdalena, Jastrzębska-Więsek, Grzegorz, Satała, Katarzyna, Kucwaj-Brysz, Annamaria, Lubelska, Monika, Głuch-Lutwin, Barbara, Mordyl, Agata, Siwek, Muhammad Jawad, Nasim, Anna, Partyka, Sylwia, Sudoł, Gniewomir, Latacz, Anna, Wesołowska, Katarzyna, Kieć-Kononowicz, and Jadwiga, Handzlik
- Subjects
Models, Molecular ,Structure-Activity Relationship ,Dose-Response Relationship, Drug ,Molecular Structure ,Cell Line, Tumor ,Receptors, Serotonin ,Image Processing, Computer-Assisted ,Animals ,Humans ,Serotonin Antagonists ,Ligands ,Locomotion ,Rats - Abstract
This research has provided the most active 5-HT
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- 2019
19. Chlorine substituents and linker topology as factors of 5-HT6R activity for novel highly active 1,3,5-triazine derivatives with procognitive properties in vivo
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Anna Partyka, Sylwia Sudoł, Gniewomir Latacz, Barbara Mordyl, Agata Doroz-Płonka, Monika Głuch-Lutwin, Magdalena Jastrzębska-Więsek, Anna Wesołowska, Wojciech Nitek, Natalia Wilczyńska, Anna Bielawska, Jadwiga Handzlik, Grzegorz Satała, Rafał Kurczab, Kamila Buzun, Katarzyna Kucwaj-Brysz, and Ewa Żesławska
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Pharmacology ,0303 health sciences ,010405 organic chemistry ,Organic Chemistry ,General Medicine ,Ring (chemistry) ,01 natural sciences ,Combinatorial chemistry ,0104 chemical sciences ,Sulfone ,03 medical and health sciences ,chemistry.chemical_compound ,chemistry ,1,3,5-Triazine ,In vivo ,Drug Discovery ,Benzene ,Linker ,Topology (chemistry) ,030304 developmental biology ,Triazine - Abstract
In the light of recent lines of evidence, 5-HT6R ligands are a promising tool for future treatment of memory impairment. Hence, this study has supplied highly potent 5-HT6R agents with procognitive effects, which represent an original chemical class of 1,3,5-triazines, different from widely studied sulfone and indole-like 5-HT6R ligands. The new compounds were rationally designed as modifications of lead, 4-(1-(2-chlorophenoxy)ethyl)-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (1), involving an introduction of: (i) two chlorines at benzene ring and (ii) varied linkers joining the triazine ring to aromatic ethers. Synthesis, in vitro and in vivo biological tests and computer-aided SAR analysis for 19 new compounds were carried out. Most of the new triazines displayed high affinity (Ki
- Published
- 2020
20. Pyrrolidin-2-one derivatives may reduce body weight in rats with diet-induced obesity
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Małgorzata Zygmunt, Marek Bednarski, Barbara Mordyl, Leszek Nowiński, Joanna Knutelska, Jacek Sapa, Magdalena Dudek, Paula Zaręba, Katarzyna Kulig, Monika Głuch-Lutwin, and Grzegorz Kazek
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Blood Glucose ,Glycerol ,Male ,0301 basic medicine ,medicine.medical_specialty ,Hydrocortisone ,Lipolysis ,Population ,Adipose tissue ,Adrenergic ,Blood Pressure ,Body Temperature ,03 medical and health sciences ,0302 clinical medicine ,Heart Rate ,Internal medicine ,medicine ,Animals ,Obesity ,Rats, Wistar ,education ,Pharmacology ,education.field_of_study ,Chemistry ,Body Weight ,Thermogenesis ,medicine.disease ,Pyrrolidinones ,Diet ,Rats ,030104 developmental biology ,Endocrinology ,Blood pressure ,Adipose Tissue ,Locomotion ,030217 neurology & neurosurgery ,medicine.drug - Abstract
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 α 2 -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 α 2 -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.
- Published
- 2016
21. Synthesis, coordination properties and biological activity of vanadium complexes with hydrazone Schiff base ligands
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Grzegorz Kazek, Janusz Szklarzewicz, Krzysztof Kruczała, Monika A. Papież, Barbara Mordyl, Dariusz Matoga, Jacek Sapa, and Anna Jurowska
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chemistry.chemical_classification ,Schiff base ,010405 organic chemistry ,Hydrazone ,Vanadium ,chemistry.chemical_element ,010402 general chemistry ,Hydrazide ,01 natural sciences ,Enol ,0104 chemical sciences ,law.invention ,Inorganic Chemistry ,chemistry.chemical_compound ,chemistry ,law ,Polymer chemistry ,Octahedral molecular geometry ,Materials Chemistry ,Physical and Theoretical Chemistry ,Cyclic voltammetry ,Electron paramagnetic resonance - Abstract
Seventeen complexes of vanadium (III-V) with hydrazido-hydrazone Schiff bases, formed from 5-bromosalicylaldehyde and different hydrazides, are described and characterized by elemental analysis, IR, UV–Vis (in solution and as reflectance spectra) and EPR spectroscopy, cyclic voltammetry and thermogravimetric measurements. The nonoxido complexes show reversible oxidation to V(V), while oxido ones only irreversible processes. The thermogravimetric measurements indicate that Schiff base is released as its components in two separated steps. The detailed EPR measurements show distorted octahedral geometry for oxido complexes with presence of two oxidovanadium(IV) centers attributed to complexes with keto- or enol- form of hydrazide, the ratio of keto : enol form was determined. The biological activity, such as inhibition of human phosphatases (PTP1B, SHP1, SHP2, LAR and CD45), cytotoxicity and glucose uptake in myocytes (C2C12) and adipocytes (3 T3-L1) of selected complexes was tested. The obtained results indicate that the strength of tyrosine phosphatases inhibition of tested complexes does not determine the strength of their antidiabetic activity demonstrated in the glucose transport to myocytes and adipocytes. This last effectiveness is much higher than for VOSO4 and BMOV.
- Published
- 2020
22. Evaluation of anticonvulsant and analgesic activity of new hybrid compounds derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and -butanamides
- Author
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Anna Rapacz, Monika Głuch-Lutwin, Michał Abram, Barbara Filipek, Barbara Mordyl, and Krzysztof Kamiński
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0301 basic medicine ,Male ,Pyrrolidines ,Cell Survival ,medicine.medical_treatment ,Analgesic ,Drug Evaluation, Preclinical ,Pain ,Pharmacology ,Motor Activity ,03 medical and health sciences ,Epilepsy ,Mice ,Random Allocation ,0302 clinical medicine ,Seizures ,medicine ,Animals ,Humans ,Hot plate test ,Valproic Acid ,Analgesics ,Neurotransmitter Agents ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Chronic pain ,Hep G2 Cells ,medicine.disease ,Disease Models, Animal ,030104 developmental biology ,Anticonvulsant ,Neurology ,Neuropathic pain ,Anticonvulsants ,Neurology (clinical) ,Levetiracetam ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Epilepsy is a chronic neurological disorder that is associated with various types of recurrent seizures, which are drug-resistant in about one third of patients. Moreover, anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic pain. Here, we investigated the anticonvulsant activity of six new hybrid compounds based on the pyrrolidine-2,5-dione scaffold in the 6 Hz corneal stimulation test with 44 mA stimulus intensity in mice, which is the model of pharmacoresistant seizures. We demonstrated that two molecules, DK-10 (11) and DK-14 (14) show higher anticonvulsant activity and similar safety profile in comparison with valproic acid and much higher in comparison with levetiracetam in the aforementioned test. The second aim of this study was to examine analgesic activity of these compounds. For this purpose, the hot plate test, the formalin test, and the oxaliplatin-induced peripheral neuropathy model were performed. Among tested agents DK-11 (12) revealed prominent antinociceptive activity at non-sedative doses in the second (inflammatory) phase of the formalin test, which is the model of tonic pain and antiallodynic activity in the oxaliplatin-induced neuropathic pain, the model of painful chemotherapy-induced peripheral neuropathy. No cytotoxic effect on hepatoma cells was observed. Compound DK-10 (11) had high affinity for voltage-gated sodium channels, whereas compound DK-11 (12) showed weak binding toward sodium and calcium voltage-gated channels and the NMDA receptor. As a result, hybrid compounds reported herein seem to be very promising broad spectrum anticonvulsant molecules with collateral analgesic activity.
- Published
- 2018
23. Structure-5-HT Receptor Affinity Relationship in a New Group of 7-Arylpiperazynylalkyl and 7-Tetrahydroisoquinolinylalkyl Derivatives of 8-Amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione
- Author
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Małgorzata Zygmunt, Barbara Mordyl, Maciej Pawłowski, Grażyna Chłoń-Rzepa, Paweł Żmudzki, Andrzej J. Bojarski, and Grzegorz Kazek
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Purine ,Chemistry ,Stereochemistry ,Substituent ,Pharmaceutical Science ,In vitro ,chemistry.chemical_compound ,Biochemistry ,THIQ ,Drug Discovery ,medicine ,Moiety ,Serotonin ,Receptor ,5-HT receptor ,medicine.drug - Abstract
In our previous paper, we have reported that some 8-alkoxy-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic activity for the serotonin 5-HT1A receptor. In order to examine the influence of the substituent in the position 8 of the purine moiety on the affinity for the serotonin 5-HT1A , 5-HT2A , and 5-HT7 receptors, a series of 7-arylpiperazynylalkyl and 7-tetrahydroisoquinolinylalkyl (THIQ) derivatives of 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for serotonin 5-HT1A , 5-HT2A , and 5-HT7 receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, functional assays for the 5-HT1A receptor were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for this receptor.
- Published
- 2015
24. RECEPTOR AFFINITY AND PHOSPHODIESTERASES 4B AND 10A ACTIVITY OF OCTAHYDRO- AND 6,7-DIMETHOXY-3,4-DIHYDRO- ISOQUINOLIN-2(1H)-YL-ALKYL DERIVATIVES OF IMIDAZO- AND PYRIMIDINO[2,1-f]PURINES
- Author
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Agnieszka, Zagórska, Beata, Gryzło, Grzegorz, Satała, Andrzej J, Bojarski, Monika, Głuch-Lutwin, Barbara, Mordyl, Grzegorz, Kazek, and Maciej, Pawłowski
- Subjects
Molecular Structure ,Phosphoric Diester Hydrolases ,Receptors, Dopamine D2 ,Imidazoles ,Pyrimidinones ,Ligands ,Transfection ,Binding, Competitive ,Radioligand Assay ,Structure-Activity Relationship ,HEK293 Cells ,Receptors, Serotonin ,Humans ,Phosphodiesterase 4 Inhibitors ,Protein Binding - Abstract
A series of octahydro- and 6,7-dimethoxy-3,4-dihydro- isoquinolin-2(1H)-yl-alkyl derivatives of imidazo- and pyrimidino[2,1-f]purines were synthesized and biologically evaluated in in vitro competition binding experiments for serotonin 5-HT(1A), 5-HT(6), 5-HT(7), and dopamine D2 receptors and inhibitory potencies for phosphodiesterases - PDE4B1 and PDE10A. The structure-activity relationships allowed to determine the structural features responsible for receptor and enzyme activity. Compound 5 (8-(4-(6,7-dimethoxy-3,4-dihydroiso- quinolin-2(1H)butyl)1,3-dimethyl-H-imidazo[2,1-f]purine-2,4(3H,8H)-dione) could be regarded as promising structure for further modification and detailed mechanistic study for obtained hybrid ligands.
- Published
- 2016
25. Arylpiperazinylalkyl derivatives of 8-amino-1,3-dimethylpurine-2,6-dione as novel multitarget 5-HT/D receptor agents with potential antipsychotic activity
- Author
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Andrzej J. Bojarski, Grzegorz Satała, Adam Bucki, Justyna Kalinowska-Tłuścik, Magdalena Jastrzębska-Więsek, Monika Głuch-Lutwin, Grażyna Chłoń-Rzepa, Marcin Kołaczkowski, Anna Partyka, Barbara Mordyl, Anna Wesołowska, and Grzegorz Kazek
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0301 basic medicine ,Pharmacology ,Agonist ,Molecular model ,medicine.drug_class ,Proton Magnetic Resonance Spectroscopy ,Antagonist ,Substituent ,General Medicine ,Combinatorial chemistry ,Partial agonist ,Piperazines ,03 medical and health sciences ,chemistry.chemical_compound ,030104 developmental biology ,chemistry ,Purines ,Dopamine receptor D2 ,Receptors, Serotonin ,Drug Discovery ,medicine ,Receptor ,5-HT receptor ,Antipsychotic Agents ,Chromatography, Liquid - Abstract
A series of new 7-arylpiperazinylalkyl-1,3-dimethyl-purine-2,6-dione derivatives with diversified 8-amino substituent in 8 position was synthesized and their 5-HT1A, 5-HT2A, 5-HT6, 5-HT7, and D2 receptor affinities were determined. The binding study allowed identifying some potent 5-HT1A/5-HT2A/5-HT7/D2 ligands. The most interesting because of their multireceptor profile were 8-piperidine (30–35) and 8-dipropylamine (45–47) analogs with four and five carbon aliphatic linkers. The selected compounds 24, 31, 34, 39, 41, 43, 45, and 46 in the functional in vitro evaluation for all targeted receptors showed significant partial D2 agonist, partial 5-HT1A agonist, and 5-HT2A antagonist properties. The advantageous in vitro affinity of compound 34 for 5-HT1A and D2 receptors has been explained by means of molecular modeling, taking into consideration its partial agonist activity towards the latter one. In behavioral studies, compounds 32 and 34 revealed antipsychotic-like properties, significantly decreasing d-amphetamine-induced hyperactivity in mice.
- Published
- 2015
26. Structure-5-HT receptor affinity relationship in a new group of 7-arylpiperazynylalkyl and 7-tetrahydroisoquinolinylalkyl derivatives of 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione
- Author
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Paweł, Żmudzki, Grażyna, Chłoń-Rzepa, Andrzej J, Bojarski, Małgorzata, Zygmunt, Grzegorz, Kazek, Barbara, Mordyl, and Maciej, Pawłowski
- Subjects
Molecular Structure ,Serotonin 5-HT1 Receptor Antagonists ,Ligands ,Binding, Competitive ,Rats ,Radioligand Assay ,Structure-Activity Relationship ,Purines ,Drug Design ,Receptors, Serotonin ,Receptor, Serotonin, 5-HT1A ,Animals ,Receptor, Serotonin, 5-HT2A ,Protein Binding - Abstract
In our previous paper, we have reported that some 8-alkoxy-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic activity for the serotonin 5-HT1A receptor. In order to examine the influence of the substituent in the position 8 of the purine moiety on the affinity for the serotonin 5-HT1A , 5-HT2A , and 5-HT7 receptors, a series of 7-arylpiperazynylalkyl and 7-tetrahydroisoquinolinylalkyl (THIQ) derivatives of 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione were synthesized. All the final compounds were investigated in in vitro competition binding experiments for serotonin 5-HT1A , 5-HT2A , and 5-HT7 receptors. The structure-affinity relationships for this group of compounds were discussed. For selected compounds, functional assays for the 5-HT1A receptor were carried out. The results of the assays indicated that these groups of derivatives possessed antagonistic activity for this receptor.
- Published
- 2014
27. A Comparison of the Anorectic Effect and Safety of the Alpha2-Adrenoceptor Ligands Guanfacine and Yohimbine in Rats with Diet-Induced Obesity
- Author
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Marek Bednarski, Barbara Mordyl, Monika Głuch-Lutwin, Leszek Nowiński, Magdalena Dudek, Joanna Knutelska, Małgorzata Zygmunt, Karolina Pytka, Grzegorz Kazek, and Jacek Sapa
- Subjects
medicine.medical_specialty ,Intrinsic activity ,lcsh:Medicine ,Stimulation ,Pharmacology ,Diet, High-Fat ,Ligands ,Partial agonist ,Heart Rate ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Appetite Depressants ,Adrenergic alpha-2 Receptor Agonists ,medicine ,Animals ,Humans ,Lipolysis ,Obesity ,lcsh:Science ,Multidisciplinary ,Chemistry ,Body Weight ,lcsh:R ,Antagonist ,Yohimbine ,Adrenergic alpha-2 Receptor Antagonists ,United States ,Guanfacine ,Rats ,Endocrinology ,Anorectic ,lcsh:Q ,Research Article ,medicine.drug - Abstract
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.
- Published
- 2015
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