283 results on '"Agata, Siwek"'
Search Results
152. Usefulness of chaotropic salt additive in RP-HPLC of organic nonionized compounds
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Jolanta Flieger, Agata Siwek, and Magdalena Pizoń
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Analyte ,Chromatography ,Sodium hexafluorophosphate ,Sodium ,chemistry.chemical_element ,Filtration and Separation ,Phosphate ,Analytical Chemistry ,chemistry.chemical_compound ,Chaotropic agent ,Column chromatography ,chemistry ,Lipophilicity ,Theoretical plate - Abstract
New synthesized 1,4-disubstituted thiosemicarbazide derivatives were analyzed in the RP system, modified with the addition of salts; chaotropic (sodium hexafluorophosphate - Na PF(6)), cosmotropic (sodium phosphate - NaH(2)PO(4)), and neutral (NaCl) on Zorbax XDB C18 column. The effect of the eluent composition on the analytes retention (k), system efficiency (N), peak symmetry (A(s)), and LOD values were all examined and compared to unmodified organic-aqueous mobile phase system. It was established that eluent modified with chaotropic salts addition was also the most advantageous according to other peak parameters such as the theoretical plates numbers and asymmetry factors. The lower LOD values were achieved in comparison to unmodified organic-aqueous eluent system. Compatibility of lipophilicity parameters calculated by the use of computer software with experimental ones measured by RP-HPLC was also the best for chaotropic modified mobile phase. To explain the observed phenomena, molecular modeling was performed for chosen representative compound in different environment representing examined mobile phase composition.
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- 2012
153. Cytotoxic effect and molecular docking of 4-ethoxycarbonylmethyl-1-(piperidin-4-ylcarbonyl)-thiosemicarbazide—a novel topoisomerase II inhibitor
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Krzysztof Bielawski, Piotr Paneth, Agata Siwek, Paweł Stączek, Anna Bielawska, and Monika Wujec
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Cell Survival ,Hydrochloride ,Stereochemistry ,Cytotoxicity ,DFT calculation ,Breast Neoplasms ,Pharmacology ,Molecular Docking Simulation ,Catalysis ,Inorganic Chemistry ,chemistry.chemical_compound ,Adenosine Triphosphate ,Human topoisomerase II ,Piperidines ,Cell Line, Tumor ,Humans ,Topoisomerase II Inhibitors ,Cytotoxic T cell ,MTT assay ,Physical and Theoretical Chemistry ,Original Paper ,biology ,Topoisomerase ,Organic Chemistry ,Thiosemicarbazide derivative ,Molecular medicine ,Semicarbazides ,Computer Science Applications ,DNA Topoisomerases, Type II ,Computational Theory and Mathematics ,chemistry ,Molecular docking ,MCF-7 Cells ,biology.protein ,Female ,Drug Screening Assays, Antitumor ,Topoisomerase-II Inhibitor - Abstract
The preliminary cytotoxic effect of 4-ethoxycarbonylmethyl-1-(piperidin-4-ylcarbonyl)-thiosemicarbazide hydrochloride (1)—a potent topoisomerase II inhibitor—was measured using a MTT assay. It was found that the compound decreased the number of viable cells in both estrogen receptor-positive MCF-7 and estrogen receptor-negative MDA-MB-231breast cancer cells, with IC50 values of 146 ± 2 and 132 ± 2 μM, respectively. To clarify the molecular basis of the inhibitory action of 1, molecular docking studies were carried out. The results suggest that 1 targets the ATP binding pocket. Figure 4-ethoxycarbonylmethyl-1-(piperidin-4-ylcarbonyl)-thiosemicarbazide hydrochloride Electronic supplementary material The online version of this article (doi:10.1007/s00894-012-1679-6) contains supplementary material, which is available to authorized users.
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- 2012
154. Chemically Homogenous Compounds with Antagonistic Properties at All α1-Adrenoceptor Subtypes but not β1-Adrenoceptor Attenuate Adrenaline-Induced Arrhythmia in Rats
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Barbara Filipek, Adrian Olczyk, Anna M. Waszkielewicz, Karolina Pytka, Joanna Śniecikowska, Magdalena Kotańska, Agnieszka Dziedziczak, Szczepan Mogilski, Klaudia Lustyk, Jarosław Śmieja, Jacek Sapa, Henryk Marona, Adam Galuszka, Małgorzata Zygmunt, Agata Siwek, and Elżbieta Żmudzka
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α1A-adrenoceptor antagonist ,Antioxidant ,Adrenergic receptor ,$\alpha_{1A}$-adrenoceptor antagonist ,medicine.medical_treatment ,chemistry.chemical_element ,030204 cardiovascular system & hematology ,Pharmacology ,Calcium ,arrhythmia ,Lipid peroxidation ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,$\alpha_{1B}$-adrenoceptor antagonist ,α1-adrenolytics ,α1D-adrenoceptor antagonist ,medicine ,Pharmacology (medical) ,$\alpha_{1}$-adrenolytics ,antiarrhythmic agents ,2-methoxyphenylpiperazine ,Receptor ,Carvedilol ,ED50 ,Original Research ,Chemistry ,lcsh:RM1-950 ,hypotensive ,lcsh:Therapeutics. Pharmacology ,α1B-adrenoceptor antagonist ,Blood pressure ,$\alpha_{1D}$-adrenoceptor antagonist ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Studies proved that among all α1-adrenoceptors, cardiac myocytes functionally express only α1A- and α1B-subtype. Scientists indicated that α1A-subtype blockade might be beneficial in restoring normal heart rhythm. Therefore, we aimed to determine the role of α1-adrenoceptors subtypes (i.e., α1A and α1B) in antiarrhythmic effect of six structurally similar derivatives of 2-methoxyphenylpiperazine. We compared the activity of studied compounds with carvedilol, which is β1- and α1-adrenoceptors blocker with antioxidant properties. To evaluate the affinity for adrenergic receptors, we used radioligand methods. We investigated selectivity at α1-adrenoceptors subtypes using functional bioassays. We tested antiarrhythmic activity in adrenaline-induced (20 μg/kg i.v.), calcium chloride-induced (140 and 25 mg/kg i.v.) and barium chloride-induced (32 and 10 mg/kg i.v.) arrhythmia models in rats. We also evaluated the influence of studied compounds on blood pressure in rats, as well as lipid peroxidation. All studied compounds showed high affinity toward α1-adrenoceptors but no affinity for β1 receptors. Biofunctional studies revealed that the tested compounds blocked α1A-stronger than α1B-adrenoceptors, but except for HBK-19 they antagonized α1A-adrenoceptor weaker than α1D-subtype. HBK-19 showed the greatest difference in pA2 values-it blocked α1A-adrenoceptors around seven-fold stronger than α1B subtype. All compounds showed prophylactic antiarrhythmic properties in adrenaline-induced arrhythmia, but only the activity of HBK-16, HBK-17, HBK-18, and HBK-19 (ED50 = 0.18-0.21) was comparable to that of carvedilol (ED50 = 0.36). All compounds reduced mortality in adrenaline-induced arrhythmia. HBK-16, HBK-17, HBK-18, and HBK-19 showed therapeutic antiarrhythmic properties in adrenaline-induced arrhythmia. None of the compounds showed activity in calcium chloride- or barium chloride-induced arrhythmias. HBK-16, HBK-17, HBK-18, and HBK-19 decreased heart rhythm at ED84. All compounds significantly lowered blood pressure in normotensive rats. HBK-18 showed the strongest hypotensive properties (the lowest active dose: 0.01 mg/kg). HBK-19 was the only compound in the group, which did not show hypotensive effect at antiarrhythmic doses. HBK-16, HBK-17, HBK-18, HBK-19 showed weak antioxidant properties. Our results indicate that the studied 2-methoxyphenylpiperazine derivatives that possessed stronger α1A-adrenolytic properties (i.e., HBK-16, HBK-17, HBK-18, and HBK-19) were the most active compounds in adrenaline-induced arrhythmia. Thus, we suggest that the potent blockade of α1A-receptor subtype is essential to attenuate adrenaline-induced arrhythmia.
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- 2016
155. Novel multi-target-directed ligands for Alzheimer's disease: Combining cholinesterase inhibitors and 5-HT
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Anna, Więckowska, Marcin, Kołaczkowski, Adam, Bucki, Justyna, Godyń, Monika, Marcinkowska, Krzysztof, Więckowski, Paula, Zaręba, Agata, Siwek, Grzegorz, Kazek, Monika, Głuch-Lutwin, Paweł, Mierzejewski, Przemysław, Bienkowski, Halina, Sienkiewicz-Jarosz, Damijan, Knez, Tomasz, Wichur, Stanislav, Gobec, and Barbara, Malawska
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Male ,Models, Molecular ,Protein Conformation ,Chemistry Techniques, Synthetic ,Ligands ,Rats ,Kinetics ,Alzheimer Disease ,Blood-Brain Barrier ,Butyrylcholinesterase ,Catalytic Domain ,Drug Design ,Receptors, Serotonin ,Acetylcholinesterase ,Animals ,Humans ,Cholinesterase Inhibitors ,Molecular Targeted Therapy ,Rats, Wistar - Abstract
As currently postulated, a complex treatment may be key to an effective therapy for Alzheimer's disease (AD). Recent clinical trials in patients with moderate AD have shown a superior effect of the combination therapy of donepezil (a selective acetylcholinesterase inhibitor) with idalopirdine (a 5-HT
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- 2016
156. Synthesis and biological evaluation of 2-fluoro and 3-trifluoromethyl-phenyl-piperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione as potential antidepressant agents
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Anna Partyka, Gabriela Starowicz, Agata Siwek, Karolina Słoczyńska, Agnieszka Zagórska, Anna Wesołowska, Marcin Kołaczkowski, Grzegorz Kazek, Elżbieta Pękala, Maciej Pawłowski, Monika Głuch-Lutwin, and Adam Bucki
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Models, Molecular ,Purinones ,Stereochemistry ,Motor Activity ,01 natural sciences ,Micellar electrokinetic chromatography ,chemistry.chemical_compound ,Mice ,Structure-Activity Relationship ,In vivo ,Drug Discovery ,Potency ,Animals ,Humans ,Swimming ,Chromatography, Micellar Electrokinetic Capillary ,Pharmacology ,Trifluoromethyl ,Behavior, Animal ,Dose-Response Relationship, Drug ,Molecular Structure ,010405 organic chemistry ,Chemistry ,Phosphoric Diester Hydrolases ,Imidazoles ,Phosphodiesterase ,General Medicine ,Antidepressive Agents ,0104 chemical sciences ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,010404 medicinal & biomolecular chemistry ,Anti-Anxiety Agents ,Receptors, Serotonin ,Lipophilicity ,Receptor, Serotonin, 5-HT1A ,Microsome ,Microsomes, Liver ,PDE10A - Abstract
A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4–21) were synthesized and evaluated for their serotonin (5-HT1A/5-HT7) receptor affinity and phosphodiesterase (PDE4B and PDE10A) inhibitor activity. The study enabled the identification of potent 5-HT1A, 5-HT7 and mixed 5-HT1A/5-HT7 receptor ligands with weak inhibitory potencies for PDE4B and PDE10A. The tests have been completed with the determination of lipophilicity and metabolic stability using micellar electrokinetic chromatography (MEKC) system and human liver microsomes (HLM) model. In preliminary pharmacological in vivo studies, selected compound 8-(5-(4-(2-fluorophenyl)piperazin-1-yl)pentyl)-1,3,7-trimethyl-1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (9) behaved as a potential antidepressant in forced swim test (FST) in mice. Moreover, potency of antianxiety effects evoked by 9 (2.5 mg/kg) is greater than that of the reference anxiolytic drug, diazepam. Molecular modeling revealed that fluorinated arylpiperazinylalkyl derivatives of 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione have major significance for the provision of lead compounds for antidepressant and/or anxiolytic application.
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- 2016
157. Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α
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Aleksandra, Rak, Vittorio, Canale, Krzysztof, Marciniec, Paweł, Żmudzki, Magdalena, Kotańska, Joanna, Knutelska, Agata, Siwek, Gabriela, Stachowicz, Marek, Bednarski, Leszek, Nowiński, Małgorzata, Zygmunt, Paweł, Zajdel, and Jacek, Sapa
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Male ,Sulfonamides ,Pyrrolidines ,Dose-Response Relationship, Drug ,Molecular Structure ,Blood Pressure ,Rats ,Structure-Activity Relationship ,Piperidines ,Receptors, Adrenergic, alpha-1 ,Adrenergic alpha-1 Receptor Antagonists ,Animals ,Humans ,Rats, Wistar ,Injections, Intraperitoneal - Abstract
A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α
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- 2016
158. Structure-5-HT/D
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Paweł, Żmudzki, Grzegorz, Satała, Grażyna, Chłoń-Rzepa, Andrzej J, Bojarski, Grzegorz, Kazek, Agata, Siwek, Anna, Gryboś, Monika, Głuch-Lutwin, Anna, Wesołowska, and Maciej, Pawłowski
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Dose-Response Relationship, Drug ,Receptors, Dopamine D2 ,Binding, Competitive ,Dopamine D2 Receptor Antagonists ,Radioligand Assay ,Structure-Activity Relationship ,Purines ,Receptor, Serotonin, 5-HT1A ,Animals ,Humans ,Calcium ,Receptor, Serotonin, 5-HT2A ,Serotonin Antagonists ,Cells, Cultured ,Adenylyl Cyclases - Abstract
In our previous papers, we have reported that some 8-amino-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione derivatives possessed high affinity and displayed agonistic, partial agonistic, or antagonistic activity for serotonin 5-HT
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- 2016
159. Antiarrhythmic activity in occlusion-reperfusion model of 1-(1H-indol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethyl]amin propan-2-ol and its enantiomers
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Marek Bednarski, Joanna Knutelska, Magdalena Dudek, Grażyna Groszek, Monika Otto, Małgorzata Zygmunt, Jacek Sapa, Leszek Nowiński, and Agata Siwek
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Male ,Antioxidant ,Indoles ,Physiology ,medicine.medical_treatment ,Myocardial Reperfusion Injury ,030204 cardiovascular system & hematology ,Pharmacology ,030226 pharmacology & pharmacy ,Antioxidants ,Lipid peroxidation ,Propanolamines ,03 medical and health sciences ,chemistry.chemical_compound ,Electrocardiography ,0302 clinical medicine ,Physiology (medical) ,medicine ,Animals ,Myocardial infarction ,Rats, Wistar ,Nicorandil ,business.industry ,Brain ,Arrhythmias, Cardiac ,Heart ,Stereoisomerism ,medicine.disease ,Malondialdehyde ,Adenosine ,Rats ,Disease Models, Animal ,chemistry ,Coronary Occlusion ,Coronary occlusion ,Anesthesia ,Calcium ,Lipid Peroxidation ,business ,Reperfusion injury ,Anti-Arrhythmia Agents ,Oxidation-Reduction ,medicine.drug - Abstract
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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- 2016
160. Synthesis and biological investigation of new equatorial (Β) stereoisomers of 3-aminotropane arylamides with atypical antipsychotic profile
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Marta Andres-Mach, Anna Gomółka, Anna Partyka, Tomasz Słowiński, Anna Wesołowska, Mirosław Zagaja, Magdalena Jastrzębska-Więsek, Jadwiga Turło, Stanisław J. Czuczwar, Franciszek Herold, Tomasz Bączek, Jacek Stefanowicz, Martyna Z. Wróbel, Jarogniew J. Łuszczki, Maria Żołnierek, Agata Siwek, Mariusz Belka, Szymon Ulenberg, and Gabriel Nowak
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Agonist ,Male ,Stereochemistry ,medicine.drug_class ,Clinical Biochemistry ,Pharmaceutical Science ,Biochemistry ,Head-twitch response ,03 medical and health sciences ,Mice ,Structure-Activity Relationship ,0302 clinical medicine ,Dopamine ,Dopamine receptor D2 ,Drug Discovery ,medicine ,Benzene Derivatives ,Moiety ,Animals ,Receptor, Serotonin, 5-HT2A ,Rats, Wistar ,Receptor ,Molecular Biology ,5-HT receptor ,Chemistry ,Receptors, Dopamine D2 ,Organic Chemistry ,Antagonist ,Stereoisomerism ,030227 psychiatry ,Dopamine D2 Receptor Antagonists ,Receptor, Serotonin, 5-HT1A ,Serotonin 5-HT2 Receptor Antagonists ,Molecular Medicine ,030217 neurology & neurosurgery ,medicine.drug ,Antipsychotic Agents ,Tropanes - Abstract
A series of novel 3β-aminotropane derivatives containing a 2-naphthalene or a 2-quinoline moiety was synthesised and evaluated for their affinity for 5-HT1A, 5-HT2A and D2 receptors. Their affinity for the receptors was in the nanomolar to micromolar range. p-Substitution (6c, 6f, 6i, 6l, 6o), as well as substitution with chlorine atoms (6g, 6h, 6i), led to a significant increase in binding affinity for D2 receptors with compounds 6f (Ki = 0.6 nM), 6c and 6i (Ki = 0.4 nM), having the highest binding affinities. m-Substituted derivatives were the most promising ligands in terms of 5-HT2A receptor binding affinity whereas 2-quinoline derivatives (10a, 10b) displayed the highest affinity for 5-HT1AR and were the most selective ligands with Ki = 62.7 nM and Ki = 30.5 nM, respectively. Finally, the selected ligands 6b, 6d, 6e, 6g, 6h, 6k, 6n and 6o, with triple binding activity for the D2, 5-HT1A and 5-HT2A receptors, were subjected to in vivo tests, such as those for induced hypothermia, climbing behaviour and the head twitch response, in order to determine their pharmacological profile. The tested ligands presented neither agonist nor antagonist properties for the 5-HT1A receptors in the induced hypothermia and lower lip retraction (LLR) tests. All tested compounds displayed antagonistic activity against 5-HT2A, with 6n and 6o being the most active. Four (6b, 6k, 6n and 6o) out of eight tested compounds could be classified as D2 antagonists. Additionally, evaluation of metabolic stability was performed for selected ligands, and introduction of halogen atoms into the benzene ring of 6h, 6k, 6n and 6o improved their metabolic stability. The project resulted in the selection of the lead compounds 6n and 6o, which had antipsychotic profiles, combining dopamine D2-receptor and 5-HT2A antagonism and metabolic stability.
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- 2016
161. Study of a mechanism responsible for potential antidepressant activity of EMD 386088, a 5-HT_6 partial agonist in rats
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Anna Partyka, Anna Wesołowska, Agata Siwek, Marcin Kołaczkowski, Irena Romańska, Jerzy Michaluk, Lucyna Antkiewicz-Michaluk, and Magdalena Jastrzębska-Więsek
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Male ,0301 basic medicine ,Indoles ,Pyridines ,Dopamine ,Striatum ,Pharmacology ,Norepinephrine ,chemistry.chemical_compound ,0302 clinical medicine ,Behavior, Animal ,biology ,Depression ,Dopaminergic ,Brain ,Monoamines metabolism ,5-HT6 receptor agonist ,General Medicine ,Antidepressive Agents ,EMD386088 ,Serotonin Receptor Agonists ,Drug Partial Agonism ,Dopamine D2 Receptor Antagonists ,EMD-386088 ,Dopamine Agonists ,Original Article ,Forced swim test ,medicine.drug ,Agonist ,Serotonin ,medicine.medical_specialty ,medicine.drug_class ,CHO Cells ,Motor Activity ,Transfection ,Partial agonist ,03 medical and health sciences ,Cricetulus ,Neurochemical ,Internal medicine ,medicine ,Animals ,Humans ,Rats, Wistar ,Dopamine transporter ,Dopamine Plasma Membrane Transport Proteins ,Dose-Response Relationship, Drug ,Receptors, Dopamine D2 ,Receptors, Dopamine D1 ,Rats ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,chemistry ,Receptors, Serotonin ,biology.protein ,030217 neurology & neurosurgery - Abstract
It was shown that 5-HT6 receptor agonists can exert pharmacological activity due to various modifications in monoamines' level and metabolism activity in rats' brain structures. This finding was correlated with antidepressant- or anxiolytic-like properties of these compounds. The study was designed to establish a possible mechanism of the antidepressant-like activity of the partial 5-HT6 receptor agonist EMD386088 (5-chloro-2-methyl-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole hydrochloride) in rats. The concentrations of monoamines (dopamine (DA), noradrenaline (NA), and serotonin (5-HT)) and the rate of their metabolism were measured ex vivo in the brain structures (hippocampus, nucleus accumbens, striatum) using high-performance liquid chromatography (HPLC). The rats were killed after the forced swim test (FST); the collected tissue samples were used to ex vivo experiments. The potency of EMD386088 to blockade dopamine transporter (DAT) was tested in a functional in vitro study. FST was used to assess the involvement of D1- and D2-like receptor subfamilies in antidepressant-like properties of EMD386088. Neurochemical data from ex vivo experiments showed that antiimmobility activity of EMD386088 may be connected with the activation of dopaminergic system, while neither noradrenergic nor serotonergic ones are involved in its effect. EMD386088 also possesses a significant affinity for DAT which may be a mechanism in the abovementioned effect. Behavioral data seem to confirm the importance of dopaminergic system activation in antidepressant-like activity of EMD386088, since this effect, observed in the FST, was abolished by the preferential D1- and D2-like receptor subfamily antagonists SCH23390 and sulpiride, respectively. Dopaminergic system is involved in antidepressant-like activity of EMD386088.
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- 2016
162. Arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines as α1-adrenergic receptor antagonist with uro-selective activity
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Małgorzata Zygmunt, Aleksandra Rak, Krzysztof Marciniec, Paweł Żmudzki, Vittorio Canale, Gabriela Stachowicz, Marek Bednarski, Jacek Sapa, Magdalena Kotańska, Leszek Nowiński, Paweł Zajdel, Joanna Knutelska, and Agata Siwek
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chemistry.chemical_classification ,Adrenergic receptor ,Intrinsic activity ,Stereochemistry ,Organic Chemistry ,Clinical Biochemistry ,030232 urology & nephrology ,Antagonist ,Pharmaceutical Science ,Biochemistry ,In vitro ,Sulfonamide ,03 medical and health sciences ,0302 clinical medicine ,chemistry ,Tamsulosin ,030220 oncology & carcinogenesis ,Drug Discovery ,medicine ,Molecular Medicine ,Selectivity ,Molecular Biology ,Biological evaluation ,medicine.drug - Abstract
A series of arylsulfonamide derivatives of (aryloxy)ethyl pyrrolidines and piperidines was synthesized to develop new α1-adrenoceptor antagonists with uroselective profile. Biological evaluation for α1- and α2-adrenorecepor showed that tested compounds 13-37 displayed high-to-moderate affinity for the α1-adrenoceptor (Ki=34-348nM) and moderate selectivity over α2-receptor subtype. Compounds with highest affinity and selectivity for α1-adrenoceptor were evaluated in vitro for their intrinsic activity toward α1A- and α1B-adrenoceptor subtypes. All compounds behaved as antagonists at both α1-adrenoceptor subtypes, displaying 2- to 6-fold functional preference to α1A-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 α1A-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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- 2016
163. Antidepressant-like activity of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and evidence for the involvement of serotonin receptor subtypes in their mechanism of action
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Magdalena Dudek, Barbara Filipek, Elżbieta Żmudzka, Marek Bednarski, Grzegorz Satała, Karolina Pytka, Anna M. Waszkielewicz, Leszek Nowiński, Henryk Marona, Andrzej J. Bojarski, Monika Kubacka, Agata Siwek, and Szczepan Mogilski
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0301 basic medicine ,Agonist ,Male ,medicine.medical_specialty ,medicine.drug_class ,Clinical Biochemistry ,Guinea Pigs ,Pharmacology ,Toxicology ,Serotonergic ,Biochemistry ,Piperazines ,Body Temperature ,03 medical and health sciences ,Behavioral Neuroscience ,Mice ,Radioligand Assay ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,Rats, Wistar ,Receptor ,Biological Psychiatry ,5-HT receptor ,Behavior, Animal ,Chemistry ,Receptor antagonist ,Antidepressive Agents ,Rats ,030104 developmental biology ,Endocrinology ,Mechanism of action ,Receptors, Serotonin ,Serotonin ,medicine.symptom ,030217 neurology & neurosurgery ,Endogenous agonist - Abstract
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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- 2016
164. HBK-7 - A new xanthone derivative and a 5-HT1A receptor antagonist with antidepressant-like properties
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Adrian Olczyk, Adam Galuszka, Karolina Pytka, Jacek Sapa, Monika Głuch-Lutwin, Agata Siwek, Henryk Marona, Barbara Filipek, Małgorzata Zygmunt, Waszkielewicz Anna Maria, Barbara Mordyl, Grzegorz Kazek, and Anna Rapacz
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Male ,0301 basic medicine ,medicine.medical_specialty ,Intrinsic activity ,medicine.drug_class ,Xanthones ,Clinical Biochemistry ,Motor Activity ,Serotonin 5-HT1 Receptor Antagonists ,Pharmacology ,Toxicology ,Serotonergic ,Biochemistry ,Piperazines ,Rotarod performance test ,Mice ,Radioligand Assay ,03 medical and health sciences ,Behavioral Neuroscience ,0302 clinical medicine ,Receptors, Adrenergic, alpha-2 ,Internal medicine ,Dopamine receptor D2 ,Avoidance Learning ,medicine ,Animals ,Biological Psychiatry ,5-HT receptor ,Serotonin Plasma Membrane Transport Proteins ,Receptors, Dopamine D2 ,Chemistry ,Immobility Response, Tonic ,Receptor antagonist ,Mianserin ,Antidepressive Agents ,030104 developmental biology ,Endocrinology ,Rotarod Performance Test ,Receptor, Serotonin, 5-HT1A ,5-HT1A receptor ,030217 neurology & neurosurgery ,medicine.drug - Abstract
Xanthone derivatives possess many biological properties, including neuroprotective, antioxidant or antidepressant-like. In this study we aimed to investigate antidepressant- and anxiolytic-like properties of a new xanthone derivative - 6-methoxy-4-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-7), as well as its possible mechanism of action, and the influence on cognitive and motor function. HBK-7 in our earlier studies showed high affinity for serotonergic 5-HT1A receptor. We determined the affinity of HBK-7 for CNS receptors and transporters using radioligand assays and examined its intrinsic activity towards 5-HT1A receptor. We evaluated antidepressant- and anxiolytic-like activity of HBK-7 in the mouse forced swim test, and four-plate test, respectively. We examined the influence on locomotor activity in mice to determine if the effect observed in the forced swim test was specific. We used step-through passive avoidance and rotarod tests to evaluate the influence of HBK-7 on cognitive and motor function, respectively. HBK-7 showed moderate affinity for dopaminergic D2 receptor and very low for serotonergic 5-HT2A, adrenergic α2 receptors, as well as serotonin transporter. Functional studies revealed that HBK-7 was a 5-HT1A receptor antagonist. HBK-7 (10mg/kg) decreased immobility time in the forced swim test. Combined treatment with sub-effective doses of HBK-7 and fluoxetine reduced immobility of mice in the forced swim test. Pretreatment with p-chlorophenylalanine and WAY-100,635 antagonized the antidepressant-like effect of HBK-7. Neither of the treatments influenced locomotor activity of mice. HBK-7 at antidepressant-like dose did not impair memory or motor coordination in mice. We demonstrated that HBK-7 was a 5-HT1A receptor antagonist with potent, comparable to mianserin, antidepressant-like activity. HBK-7 mediated its effect through serotonergic system and its antidepressant-like action required the activation of 5-HT1A receptors. At active dose it did not influence cognitive and motor function. Since 5-HT1A receptor antagonists may accelerate the occurrence of antidepressant effect, our findings highlight their potential as future antidepressants.
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- 2016
165. Design, synthesis, and biological evaluation of fluorinated imidazo[1,2-a]pyridine derivatives with potential antipsychotic activity
- Author
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Anna Wesołowska, Agata Siwek, Elżbieta Pękala, Barbara Mordyl, Gabriela Starowicz, Przemyslaw Bienkowski, Monika Marcinkowska, Jerzy Samochowiec, Paweł Mierzejewski, Tadeusz Karcz, Adam Bucki, Paulina Kubowicz, Marcin Kołaczkowski, Maciej Pawłowski, and Krzysztof Kamiński
- Subjects
Psychosis ,Zolpidem ,Allosteric modulator ,Halogenation ,Stereochemistry ,Cell Survival ,Pyridines ,medicine.medical_treatment ,Chemistry Techniques, Synthetic ,Pharmacology ,01 natural sciences ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Allosteric Regulation ,Drug Discovery ,Pyridine ,medicine ,Animals ,Humans ,Receptor ,Antipsychotic ,Binding Sites ,010405 organic chemistry ,Organic Chemistry ,General Medicine ,Hep G2 Cells ,medicine.disease ,Receptors, GABA-A ,0104 chemical sciences ,Electrophysiological Phenomena ,Rats ,Design synthesis ,chemistry ,Mechanism of action ,Drug Design ,medicine.symptom ,030217 neurology & neurosurgery ,medicine.drug ,Antipsychotic Agents - Abstract
Based on our recent finding that α1 selective GABA-A receptor potentiator—zolpidem—(a hypnotic drug) exerts antipsychotic-like effects in rats, we developed a series of fluorinated imidazo[1,2-a]pyridine derivatives as potential novel antipsychotic agents. The selected compounds displayed high affinity and positive allosteric modulator properties at the GABA-A receptor, enhanced metabolic stability and lack of hepatotoxicity. The most promising compound 2-(2-(4-fluorophenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)-N,N-dimethylethanamide (26) showed antipsychotic-like activity in amphetamine-induced hyperlocomotion test in rats (MED = 1 mg/kg) and was characterized by a longer duration of antipsychotic-like activity as compared to zolpidem. These results are an encouraging example of a compound with non-dopaminergic mechanism of action displaying antipsychotic activity and are a point of entry for the future studies in this field.
- Published
- 2016
166. Antibacterial Characterization of 1-benzoyl-4-arylthiosemicarbazides and the study of their structure-activity relationship
- Author
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Edyta Kusmierz, Agata Siwek, Anna Malm, Urszula Kosikowska, and Monika Wujec
- Subjects
Chemistry ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Structure–activity relationship ,Combinatorial chemistry ,Characterization (materials science) - Published
- 2012
167. Synthesis and SAR-study for novel arylpiperazine derivatives of 5-arylidenehydantoin with α1-adrenoceptor antagonistic properties
- Author
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Agata Siwek, Renata Wójcik, Magdalena Jastrzębska-Więsek, Ewa Szymańska, Jadwiga Handzlik, Andrzej Fruziński, Anna Dela, Katarzyna Kieć-Kononowicz, Barbara Filipek, and Janina Karolak-Wojciechowska
- Subjects
Stereochemistry ,Hydrochloride ,Organic Chemistry ,Clinical Biochemistry ,Pharmaceutical Science ,Hydantoin ,Crystal structure ,Biochemistry ,Molecular mechanics ,Affinities ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Molecular Medicine ,Mitsunobu reaction ,Pharmacophore ,Molecular Biology ,Arylpiperazine derivatives - Abstract
The study is focused on a series of 5-arylidenehydantoin derivatives with a phenylpiperazine-hydroxypropyl fragment at N3 of the hydantoin ring. The compounds were assessed on their affinity for α1-adrenoceptors and evaluated in functional bioassays for their antagonistic properties. Crystal structures of (Z)-5-(4-chlorobenzylidene)-3-(3-(4-(2-ethoxyphenyl)piperazin-1-yl)-2-hydroxypropyl)imidazolidine-2,4-dione (7) and hydrochloride of (Z)-5-(4-chlorobenzylidene)-3-(2-hydroxy-3-(4-(2-methoxyphenyl)piperazin-1-yl)propyl)imidazolidine-2,4-dione (10a) were solved using the X-ray diffraction method. Classical molecular mechanics (MMFFs force field, MCMM, MacroModel) were used to predict 3D structure of compounds 5a–18a using a crystal structure of 7. SAR analysis was performed on the basis of Barbaro’s pharmacophore model and structural properties of previously investigated α1-adrenoceptor antagonists possessing a hydantoin fragment. Most of the compounds exhibited significant affinities for α1-ARs in nanomolar range (40–290 nM). The highest activities (Ki 2,4-di CH3O>4-Cl>2,3-di CH3O>H>4-N(CH3)2.
- Published
- 2012
168. Does dehydrocyclization of 4-benzoylthiosemicarbazides in acetic acid lead to s-triazoles or thiadiazoles?
- Author
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Urszula Kosikowska, Piotr Paneth, Stefan Jankowski, Paweł Stączek, Agata Siwek, and Anna Malm
- Subjects
Acetic acid ,chemistry.chemical_compound ,chemistry ,Thiadiazoles ,Triazole ,Organic chemistry ,Physical and Theoretical Chemistry ,Condensed Matter Physics - Abstract
Ever since the recognition of strong pharmaceutical activities of triazoles and thiadiazoles, these scaffolds have been the subject of vigorous studies. One of the best strategies for synthesis of these azoles is dehydrocyclization of 1,4-disubstituted thiosemicarbazides, which leads to s-triazoles in alkaline media, whereas in strong acidic media 1,3,4-thiadiazoles are formed. However, the literature is riddled with contradictory communications regarding the nature of the products of such reactions under mild acidic conditions. As these compounds are not amenable to X-ray analysis, we have resorted to NMR and theoretical modelling to resolve this discrepancy. In this article, we present arguments indicating that dehydrocyclization of 4-benzoylthiosemicarbazides in glacial acetic acid leads to thiadiazole derivatives. These structural findings are augmented by studies of bioactivity of a few members of the studied class of compounds.
- Published
- 2012
169. Design, synthesis, anticonvulsant, and antiarrhythmic properties of novel N-Mannich base and amide derivatives of β-tetralinohydantoin
- Author
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Agata Siwek, Marek Bednarski, Hanna Byrtus, Anna Czopek, Jacek Sapa, Maciej Pawłowski, Grzegorz Kazek, and Agnieszka Zagórska
- Subjects
Phenytoin ,Male ,Stereochemistry ,medicine.medical_treatment ,Hydantoin ,Mannich base ,Pharmacology ,010402 general chemistry ,01 natural sciences ,Mannich Bases ,Rats, Sprague-Dawley ,chemistry.chemical_compound ,Structure-Activity Relationship ,Seizures ,Amide ,medicine ,Moiety ,Animals ,Electroshock ,010405 organic chemistry ,Chemistry ,Neurotoxicity ,General Medicine ,medicine.disease ,Amides ,0104 chemical sciences ,Rats ,Disease Models, Animal ,Anticonvulsant ,Drug Design ,Rotarod Performance Test ,Pentylenetetrazole ,Amine gas treating ,Anticonvulsants ,Neurotoxicity Syndromes ,Anti-Arrhythmia Agents ,medicine.drug - Abstract
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 (ED 50 16.3 mg/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.
- Published
- 2015
170. Synthesis and antimicrobial evaluation of new 1-{[4-(4-Halogenophenyl)-4H-1,2,4- triazol-3-yl]sulfanyl}acetyl-4-substituted thiosemicarbazides and products of their cyclization
- Author
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Urszula Kosikowska, Anna Malm, Nazar Trotsko, Monika Wujec, Jakub Krol, and Agata Siwek
- Subjects
biology ,Heteroatom ,General Chemistry ,biology.organism_classification ,Antimicrobial ,Medicinal chemistry ,In vitro ,Acetic acid ,chemistry.chemical_compound ,Minimum inhibitory concentration ,chemistry ,Sulfanyl ,Isothiocyanate ,Bacteria - Abstract
By the reaction of hydrazides of 4-(4-halogenophenyl)-4H-1,2,4-triazol-3-yl-sulfanyl acetic acid with isothiocyanate, 1-acyl-4-substituted thiosemicarbazide derivatives (7–19) were obtained. The cyclization of compounds (7–19) in the presence of 2% NaOH led to the formation of compounds (20–26) containing two 1,2,4-triazole rings connected by a methylenesulfanyl group. The new compounds were tested for their in vitro antimicrobial activity. Some of the tested compounds (9, 12, 18, 21, 22) showed activity against the reference strains of Gram-positive bacteria with the MIC (minimal inhibitory concentration) = 125 to >1000 μg/mL. © 2011 Wiley Periodicals, Inc. Heteroatom Chem 23:117–121, 2012; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20758
- Published
- 2011
171. Synthesis, X-ray crystal structure and theoretical study of 4-ethyl-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione; structural comparison with its aromatic analogs
- Author
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Agata Siwek and Irena Wawrzycka-Gorczyca
- Subjects
Inorganic Chemistry ,Crystallography ,Chemistry ,Stereochemistry ,X-ray crystallography ,X-ray ,1 2 4 triazole 3 thione ,General Materials Science ,Crystal structure ,Condensed Matter Physics - Abstract
The crystal structure of 4-ethyl-5-(2-thienyl)-2,4-dihydro-3H-1,2,4-triazole-3-thione (1) was determinäed. The compound crystallizes in the monoclinic space group P21/n (Z = 4) with a = 8.679(2), b = 7.873(2), c = 14.657(3) Å, β = 105.56(3)° and V = 964.8(4) Å3. Its molecular and crystal structure was compared with three aromatic analogs. In three crystal structures of 2,4-dihydro-3H-1,2,4-triazole-3-thione derivatives, Ntriazole—H · · · S(=C) dimer as the main structural motif is formed, while in one Ntriazole—H · · · S hydrogen bonds connect molecules to make helix arrangement. Moreover, in 1, Cethyl—H · · · S(=C), Sthione · · · Sthiophene and πthiophene · · · πtriazole interactions are observed; there are not N—H · · · N hydrogen bonds. NMR in DMSO and IR experiments confirmed the compound to exist as the thione tautomer. We carried out extensive conformational searches for 1 at the molecular mechanics level in order to compare structures obtained from different force fields with the experimental results.
- Published
- 2011
172. Synthesis and antimicrobial activity of thiosemicarbazides, s-triazoles and their Mannich bases bearing 3-chlorophenyl moiety
- Author
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Anna Malm, Urszula Kosikowska, Agata Siwek, Monika Wujec, and Tomasz Plech
- Subjects
Pharmacology ,Bacteria ,Aerobic bacteria ,Aryl ,Organic Chemistry ,Microbial Sensitivity Tests ,General Medicine ,Mannich base ,Triazoles ,Hydrazide ,Chemical synthesis ,Anti-Bacterial Agents ,Semicarbazides ,Mannich Bases ,chemistry.chemical_compound ,chemistry ,Drug Discovery ,Humans ,Organic chemistry ,Moiety ,Antibacterial activity ,Antibacterial agent - Abstract
A fast and efficient synthesis of some 1,4-disubstituted thiosemicarbazide derivatives is described. The reaction of 3-chlorobenzoic acid hydrazide with various aryl isothiocyanates gave thiosemicarbazide derivatives (1-11) in good yield. The cyclization of compounds (1-11) in the presence of 2% NaOH resulted in the formation of compounds (12-22) containing the 1,2,4-triazole ring. A series of new Mannich bases (23-33) related to the structure of 1,2,4-triazole has been also synthesized. All of these compounds were tested for their in vitro antibacterial activity against the reference strains of aerobic bacteria - 6 Gram-positive and 3 Gram-negative ones; 12 Staphylococcus aureus clinical isolates were also examined. An attempt was made to clarify the influence of the nature/position of substituents on antibacterial activity of compounds described.
- Published
- 2011
173. Synthesis and crystal structure of N-butyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-thiadiazol-2-amine and 5-isoquinolin-3-yl-N-(2-methylphenyl)-1,3,4-thiadiazol-2-amine
- Author
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Urszula Kosikowska, Agata Siwek, Irena Wawrzycka-Gorczyca, and Anna Malm
- Subjects
Chemistry ,Hydrogen bond ,Dimer ,Space group ,Crystal structure ,Condensed Matter Physics ,Inorganic Chemistry ,Crystallography ,chemistry.chemical_compound ,Molecule ,General Materials Science ,Amine gas treating ,Isoquinoline ,Monoclinic crystal system - Abstract
The synthesis, characterization, and X-ray crystal structure of two new compounds were determined: N-butyl-5-(4-methyl-1,2,3-thiadiazol-5-yl)-1,3,4-thiadiazol-2-amine (1) crystallizes in the monoclinic space group P21/n with a = 5.222(1), b = 15.010(3), c = 15.343(3) Å, β = 93.30(3)°, Z = 4 and 5-isoquinolin-3-yl-N-(2-methylphenyl)-1,3,4-thiadiazol-2-amine (2) crystallizes in the monoclinic space group P21/c with a = 7.455(2), b = 17.113(5), c = 12.199(3) Å, β = 94.68(2)°, Z = 4. In both structures, intermolecular N—H···N hydrogen bonds link two neighbouring molecules into a centrosymmetric R2 2(8) dimer.
- Published
- 2010
174. Synthesis and In Vitro Antimicrobial Evaluation of 4-alkyl/aryl-1-(3-phenoxypropionyl)-thiosemicarbazides
- Author
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Edyta Kusmierz, Agata Siwek, Joanna Stefańska, and Monika Wujec
- Subjects
chemistry.chemical_classification ,chemistry.chemical_compound ,chemistry ,Aryl ,Drug Discovery ,Pharmaceutical Science ,Molecular Medicine ,Antimicrobial ,Combinatorial chemistry ,Alkyl ,In vitro - Published
- 2010
175. Biological and docking studies of topoisomerase IV inhibition by thiosemicarbazides
- Author
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Agata Siwek, Anna Malm, Stefan Jankowski, Urszula Kosikowska, Paweł Stączek, Monika Wujec, Joanna Stefańska, and Piotr Paneth
- Subjects
DNA Topoisomerase IV ,Models, Molecular ,Staphylococcus aureus ,Topoisomerase IV ,Stereochemistry ,Molecular Conformation ,Microbial Sensitivity Tests ,DNA gyrase ,Catalysis ,Inorganic Chemistry ,Bacillus cereus ,Disk Diffusion Antimicrobial Tests ,Staphylococcus epidermidis ,Computer Simulation ,Physical and Theoretical Chemistry ,Binding site ,Enzyme Assays ,Indole test ,Binding Sites ,biology ,Topoisomerase ,Organic Chemistry ,Imidazoles ,Anti-Bacterial Agents ,Semicarbazides ,Computer Science Applications ,Micrococcus luteus ,Computational Theory and Mathematics ,Biochemistry ,Docking (molecular) ,Enzyme inhibitor ,biology.protein ,Antibacterial activity ,Bacillus subtilis ,Protein Binding - Abstract
4-Benzoyl-1-(4-methyl-imidazol-5-yl)-carbonylthiosemicarbazide (1) was synthesized, and its antibacterial and type IIA topoisomerase (DNA gyrase and topoisomerase IV) activity evaluated. (1) was found to have high therapeutic potential against opportunistic Gram-positive bacteria, and inhibitory activity against topoisomerase IV (IC(50)=90 μM) but not against DNA gyrase. An increase in activity against topoisomerase IV (IC(50)=14 μM) was observed when the imidazole moiety of (1) was replaced with the indole group in 4-benzoyl-1-(indol-2-yl)-carbonylthiosemicarbazide (2). However, (2) showed only weak antibacterial activity. Although the results of the bacterial type IIA topoisomerases inhibition study did not parallel antibacterial activities, our observations strongly imply that a 4-benzoylthiosemicarbazide scaffold can be developed into an efficient Gram-positive antibacterial targeting topoisomerase IV. The difference in activity against type IIA topoisomerases between (1) and (2) was further investigated by docking studies, which suggested that these compounds target the ATP binding pocket.
- Published
- 2010
176. GABAergic dysfunction in mGlu7 receptor-deficient mice as reflected by decreased levels of glutamic acid decarboxylase 65 and 67kDa and increased reelin proteins in the hippocampus
- Author
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Joanna M. Wierońska, Gabriel Nowak, Agata Siwek, Piotr Brański, Małgorzata Dybała, and Andrzej Pilc
- Subjects
Male ,medicine.medical_specialty ,metabotropic glutamate receptors ,Cell Adhesion Molecules, Neuronal ,Glutamate decarboxylase ,Nerve Tissue Proteins ,Receptors, Metabotropic Glutamate ,Tritium ,Hippocampus ,GABA Antagonists ,Mice ,GABA ,Organophosphorus Compounds ,GABA$_{B}$ ,Internal medicine ,reelin ,medicine ,Animals ,RNA, Messenger ,Reelin ,Molecular Biology ,gamma-Aminobutyric Acid ,Mice, Knockout ,Neurons ,Analysis of Variance ,Extracellular Matrix Proteins ,biology ,Glutamate Decarboxylase ,GAD ,General Neuroscience ,Serine Endopeptidases ,Glutamate receptor ,Metabotropic glutamate receptor 6 ,DAB1 ,Mice, Inbred C57BL ,Reelin Protein ,Endocrinology ,Metabotropic receptor ,Gene Expression Regulation ,nervous system ,Metabotropic glutamate receptor ,biology.protein ,GABAergic ,Neurology (clinical) ,Protein Binding ,Developmental Biology - Abstract
Glutamate is the main excitatory neurotransmitter in the brain, while gamma-aminobutyric acid (GABA) is a primary inhibitory neuromodulator. Both amino acids act through ionotropic and metabotropic receptors that are widely distributed in the central nervous system. There are at least eight subtypes of metabotropic glutamate receptors (mGlu), which have been divided into three groups (mGlu I, II, and III). The mGlu7 receptor subtype, which belongs to the mGlu III group, seems to play a special role, as it is abundant in brain structures that are known to be responsible for antidepressant and/or anxiolytic activity of drugs. In GABAergic neurons, GABA is synthesised from glutamate by the pyridoxal phosphate (PLP)-dependent enzyme glutamic acid decarboxylase (GAD). It is expressed as two major isoforms, GAD65 and GAD67, responsible for the synthesis of the vesicular and cytoplasmic pool of neurotransmitter, respectively. Moreover, GABAergic neurons express a variety of proteins such as reelin, involved in synaptic transmission and plasticity. The aim of our study was to investigate the regulation of GABA synthesis and the level of modulatory receptor for GABA in mice lacking mGlu7 receptor for glutamate. The levels of GAD mRNA, GADs, and reelin proteins in the hippocampi of mGlu7-/- and mGlu7-/+ mice were measured using in situ hybridisation, immunohistochemistry, and Western blotting (WB). GAD mRNAs in the CA and DG regions of the hippocampus were measured separately. The levels of GAD65, GAD67, and reelin proteins were determined in the homogenates using WB, and the number of stained neurons was estimated using a stereological method of counting. GABA(B) receptor level was measured using a radioligand binding assay. Our results show that the mRNA and protein levels of both GADs were decreased in the hippocampi of animals lacking the mGlu7 receptor. Decreased levels of GAD67 mRNA were found in both the CA and DG regions, while the decrease in GAD65 mRNA was observed mainly in the CA region of the hippocampus. The protein levels of GAD65 was lowered in mGlu7-/- animals only, while GAD67 and GABA(B) receptor number were decreased in both mGlu7+/- and mGlu7-/- mice when measured in the whole hippocampus. In contrast, reelin was shown to be increased both in mGlu7-/+ and mGlu7-/- mice. The results suggest that mGlu7 receptor is involved in the regulation of GABAergic system activity at the level of GABA synthesised enzymes, specific proteins expressed by GABAergic neurons and metabotropic receptor for GABA.
- Published
- 2010
177. Study of direction of cyclization of 1-azolil-4-aryl/alkyl-thiosemicarbazides
- Author
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Agata Siwek, Irena Wawrzycka-Gorczyca, Maria Dobosz, and Monika Wujec
- Subjects
chemistry.chemical_classification ,Aryl ,Heteroatom ,Triazole ,General Chemistry ,Medicinal chemistry ,chemistry.chemical_compound ,chemistry ,Organic chemistry ,Azole ,Moiety ,Imidazole ,Alkyl ,Pyrrole - Abstract
On a four series of 1-azolil-4-aryl/alkyl-thiosemicabazides, a study on the influence of azole moiety on the capability for intramolecular cyclization and its direction was carried out. It was found that for 4-aryl/alkyl-thiosemicabazides with triazole, imidazole, or pyrrole moiety at N-1 nitrogen atom possible products were only s-triazoles, both in alkaline and acidic medium. Successful dehydrocyclization of 1-azolil-4-aryl/alkyl-thiosemicarbazides leading to a thiadiazole has been documented only for a series of 1-(4-methyl-1,2,3-thiadiazol-5-yl-carbonyl)-4-aryl/alkyl-thiosemicarbazides. It can be speculative that the determination of pKa value of oxygen atom of 1-azolil-4-aryl/alkyl-thiosemicarbazide can be a very valuable parameter in the prediction of the possibility of dehydrocyclization to form thiadiazole. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:521–532, 2010; View this article online at wileyonlinelibrary.com. DOI 10.1002/hc.20643
- Published
- 2010
178. Structure-activity relationship of s-triazoles and thiadiazoles as analgesics
- Author
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Edyta Kuśmierz, Agata Siwek, Tomasz Plech, Ewa Jagiełło-Wójtowicz, Anna Chodkowska, and Monika Wujec
- Subjects
Behavioral test ,Thiadiazoles ,Stereochemistry ,Chemistry ,Molecular descriptor ,Principal component analysis ,Structure–activity relationship ,General Chemistry ,Analgesic agents - Abstract
The influence of s-triazoles (6–9) and thiadiazoles (10–11) on the central nervous system of mice in some behavioral tests was investigated. It was found that compounds (10) and (11) are the possible candidates for further development as analgesic agents. The correlation between the molecular descriptors and analgesic potential has been studied by using the pattern recognition methods: principal component analysis (PCA) and hierarchical cluster analysis (HCA). Our results, however, showed that the relationship between molecular descriptors and analgesic activity of s-triazoles and thiadiazoles cannot be easily explained on the basis of PCA and HCA. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:256–264, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20605
- Published
- 2010
179. Antimicrobial Properties of 4-Aryl-3-(2-methyl-furan-3-yl)-Δ2-1,2,4-triazoline-5-thiones
- Author
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Agata Siwek, Joanna Stefańska, Monika Wujec, and Piotr Paneth
- Subjects
Inorganic Chemistry ,chemistry.chemical_compound ,Quantitative structure–activity relationship ,chemistry ,Furan ,Aryl ,Organic Chemistry ,Intramolecular cyclization ,Organic chemistry ,Antimicrobial ,Biochemistry - Abstract
Four 4-aryl-3-(2-methyl-furan-3-yl)-Δ2-1,2,4-triazole-5-thiones were synthesized by intramolecular cyclization of 4-aryl-1-[(2-methyl-furan-3-yl)carbonyl]thiosemicarbazides in alkaline medium. The antimicrobial activity of the synthesized triazoles was evaluated. Semiempirical calculations of geometries, energies, and QSAR parameters have been determined in the hope of gaining insight into different biological activities of closely related isomers. New RM1 parameterization has been shown to perform very well for this class of compounds.
- Published
- 2009
180. Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity: Part 2☆
- Author
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Franciszek, Herold, Łukasz, Izbicki, Andrzej, Chodkowski, Maciej, Dawidowski, Marek, Król, Jerzy, Kleps, Jadwiga, Turło, Irena, Wolska, Gabriel, Nowak, Katarzyna, Stachowicz, Małgorzata, Dybała, Agata, Siwek, Mateusz, Nowak, Elzbieta, Pieniazek, Małgorzata, Jarończyk, Ingebrigt, Sylte, and Aleksander P, Mazurek
- Subjects
Male ,Models, Molecular ,Serotonin Plasma Membrane Transport Proteins ,Pharmacology ,Behavior, Animal ,Organic Chemistry ,pyrido[1,2-c]pyrimidines ,Hypothermia ,General Medicine ,Motor Activity ,Antidepressive Agents ,Body Temperature ,Mice ,Structure-Activity Relationship ,Pyrimidines ,antidepressants ,Receptor, Serotonin, 5-HT1A ,Drug Discovery ,Animals ,dual 5-HT$_{1A}$/SERT activity ,Selective Serotonin Reuptake Inhibitors ,Protein Binding - Abstract
Derivatives of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine were synthesized. These compounds contain the 3-(4-piperidyl)-1H-indole residue or its 5-methoxy or 2-methyl derivative. In vitro binding tests were performed to determine the affinity of the compounds for the 5-HT(1A) receptor and serotonin transporter (SERT) proteins in the rat brain cortex. In vivo studies, particularly the inducible hypothermia test and forced swimming test, were conducted to determine agonistic/antagonistic activity with pre- and postsynaptic 5-HT(1A) receptors. Molecular modeling techniques were used to determine the binding modes of the selected compounds at the 5-HT(1A) receptor and SERT. The SAR analysis showed that the presence of the 3-(4-piperidyl)-1H-indole group or its 5-methoxy derivative, as well as a para substitution with -OCH(3) or -F in the aryl ring of 4-aryl-5,6,7,8-tetrahydro-pyrido[1,2-c]pyrimidine, results in an increased affinity for both the 5-HT(1A) receptors and SERT. In contrast, the presence of the 2-methyl-3-(4-piperidyl)-1H-indole group resulted in a considerable decrease in binding affinity.
- Published
- 2009
181. New Derivatives of Thiosemicarbazide and 1,2,4-Triazoline-5-thione with Potential Antimicrobial Activity
- Author
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Agata Siwek, Anna Malm, Urszula Kosikowska, and Monika Wujec
- Subjects
biology ,Aerobic bacteria ,Organic Chemistry ,Antimicrobial ,Hydrazide ,biology.organism_classification ,Biochemistry ,In vitro ,Inorganic Chemistry ,chemistry.chemical_compound ,Acetic acid ,chemistry ,Organic chemistry ,Micrococcus luteus ,Antibacterial activity - Abstract
In the reaction of the hydrazide of (4-nitroimidazol-1-yl)acetic acid 1 with isothiocyanates, the respective thiosemicarbazide derivatives 2–6 were obtained. Further cyclization with 2% NaOH led to the formation of 3-[(4-nitroimidazol-1-yl)-methyl]-4-substituted-1,2,4-triazoline-5-thiones 7–11 . The structures of all new products were confirmed by analytical and spectroscopic methods. Six compounds 2–5 , 8 , and 10 were screened for their in vitro activity against some species of aerobic bacteria and fungi. Compound 3 appears to be a promising precursor of agents with antibacterial activity against Micrococcus luteus.
- Published
- 2009
182. Synthesis, structure and investigations of tuberculosis inhibition activities of new 4-methyl-1-substituted-1H-1,2,4-triazole-5(4H)-thione
- Author
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Agata Siwek, Monika Wujec, Liliana Mazur, Marta Swatko-Ossor, and Zofia Rzaczynska
- Subjects
biology ,Stereochemistry ,Chemistry ,Mycobacterium smegmatis ,Organic Chemistry ,1,2,4-Triazole ,Carbon-13 NMR ,biology.organism_classification ,Acylation ,chemistry.chemical_compound ,Proton NMR ,Antibacterial activity ,Mycobacterium phlei ,Mycobacterium - Abstract
By the reaction aminomethylation, chloromethylation and acylation of 4-methyl-4H-1,2,4-triazole-3-thiol, 4-methyl-1-substituted-1H-1,2,4-triazole-5(4H)-thione 1-8 were obtained. Molecular structure of the obtained compounds was confirmed by an elemental analysis, IR, 1H NMR and 13C NMR spectra and additionally by X-ray analysis for 2. Six new compounds 1,2,4-7 were tested for antibacterial activity against Mycobacterium smegmatis, Mycobacterium phlei and avirulent strain Mycobacterium H37Ra.
- Published
- 2008
183. Chemical and Pharmacological Properties of 3-(Thiophen-2-yl)-4-substituted-Δ2-1,2,4-triazoline-5-thiones
- Author
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Maria Dobosz, Piotr Paneth, Agata Siwek, Monika Wujec, Ewa Jagiełło-Wójtowicz, Anna Chodkowska, and Agnieszka Kleinrok
- Subjects
Inorganic Chemistry ,medicine.anatomical_structure ,Behavioral test ,Chemistry ,Stereochemistry ,Organic Chemistry ,Central nervous system ,medicine ,Intramolecular cyclization ,Cns activity ,Biochemistry ,CHELPG - Abstract
Three 3-(thiophen-2-yl)-4-substituted-Δ 2 -1,2,4-triazoline-5-thiones were synthesized by intramolecular cyclization of 1-(thiophen-2-ylcarbonyl)-4-substituted thiosemicarbazides in alkaline medium. Their effects on the central nervous system (CNS) of mice in some behavioral tests were investigated. All investigated compounds displayed antinociceptive activity. The correlation between the structural features and bioactivity has been discussed.
- Published
- 2008
184. Kinetic Isotope Effects on Dehalogenations at an Aromatic Carbon
- Author
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Lukasz Szatkowski, Agnieszka Dybala-Defratyka, Monika Wujec, Piotr Paneth, Rafał Kamiński, and Agata Siwek
- Subjects
Models, Molecular ,Halogenation ,Hydrolases ,Inorganic chemistry ,Kinetics ,chemistry.chemical_element ,Fractionation ,Kinetic energy ,Hydrocarbons, Aromatic ,Catalysis ,Hemoglobins ,Isotopes ,Computational chemistry ,Kinetic isotope effect ,Chlorine ,Environmental Chemistry ,Phenylalanine Ammonia-Lyase ,Chemistry ,Hydrolysis ,General Chemistry ,Carbon ,Peroxidases ,Atrazine ,Chlorophenols - Abstract
In order to interpret the observed isotopic fractionation it is necessaryto understand its relationship with the isotope effect(s) on steps that occur during the conversion of the initial reactant to the final product. We examine this relationship from the biochemical point of view and elaborate on the consequences of the assumptions that it is based on. We illustrate the discrepancies between theoretical and experimental interpretation of kinetic isotope effects on examples of dehalogenation reactions that occur at an aromatic carbon atom. The examples include 4-chlorobenzoyl-CoA dehalogenase-catalyzed conversion of 4-chlorobenzoyl-CoA to 4-hydroxybenzoyl-CoA, dehaloperoxidase-catalyzed conversion of 2,4,6-trichlorophenol to 2,6-dichloroquinone, and spontaneous hydrolysis of atrazine at pH 12. For this latter reaction we have measured the chlorine kinetic isotope effect and estimated its value theoretically at the DFT level of theory. Results of chlorine kinetic isotope effects suggest that the studied dechlorination reactions proceed in a single step with significant weakening of the carbon-chlorine bond in the transition state.
- Published
- 2008
185. Synthesis and pharmacological properties of 3-(2-methyl-furan-3-yl)-4-substituted-Δ2-1,2,4-triazoline-5-thiones
- Author
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Monika Wujec, Ewa Jagiełło-Wójtowicz, Agnieszka Kleinrok, Maria Dobosz, Agata Siwek, Piotr Paneth, and Anna Chodkowska
- Subjects
chemistry.chemical_compound ,chemistry ,Stereochemistry ,Furan ,Materials Chemistry ,General Chemistry ,Cns activity ,Hydrazide ,Medicinal chemistry - Abstract
By the reaction of 2-methyl-furan-3-carboxylic acid hydrazide with isothiocyanates, 1-[(2-methyl-furan-3-yl)carbonyl]-4-substituted thiosemicarbazides 1 were obtained. Further cyclization with 2% NaOH led to the formation of 3-(2-methyl-furan-3-yl)-4-substituted-Δ2-1,2,4-triazoline-5-thiones 2. The pharmacological effects of 2 on the central nervous system in mice were investigated. Strong antinociceptive properties of the investigated derivatives were observed in a wide range of doses.
- Published
- 2008
186. Thiol–thione tautomeric forms recognition on the example of 4-[3-(2-methyl-furan-3-yl)-5-thioxo-1,2,4-triazolin-4-yl]acetic acid
- Author
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Irena Wawrzycka-Gorczyca, Piotr Paneth, Monika Wujec, Agata Siwek, and Maria Dobosz
- Subjects
NMR spectra database ,chemistry.chemical_classification ,Acetic acid ,chemistry.chemical_compound ,Chemistry ,Furan ,Heteroatom ,Solid-state ,Thiol ,Organic chemistry ,General Chemistry ,Medicinal chemistry ,Tautomer - Abstract
The synthesis of 4-[3-(2-methyl-furan-3-yl)-5-thioxo-1,2,4-triazolin-4-yl]acetic acid, its structural study in the solid state, and the thiol–thione tautomeric recognition on the basis of spectroscopic data and theoretical calculations are presented. It is shown that NMR spectra, especially 13C and 15N, are indicative of the actual tautomeric form whereas vibrational data can be ambiguous. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:337–344, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20433
- Published
- 2008
187. Computational studies of the cyclization of thiosemicarbazides
- Author
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Piotr Paneth and Agata Siwek
- Subjects
Chemistry ,Organic Chemistry ,Substituent ,Ring (chemistry) ,Photochemistry ,Medicinal chemistry ,chemistry.chemical_compound ,Acetic acid ,Imidazolidine ,Anhydrous ,Molecule ,Moiety ,Physical and Theoretical Chemistry ,Derivative (chemistry) - Abstract
While typically cyclodehydration of thiosemicarbazides in acidic media leads to 1,3,4-thiadiazoles, we have recently shown that under reflux conditions in anhydrous acetic acid the cyclization yields an imidazolidine derivative. The mechanism of this reaction has been characterized theoretically. Calculations indicate that this direction, facilitated by the presence of the CH2CO2 moiety in the N4 substituent is favored over the direction leading toward the thiadiazole product. Formation of the CN bond that closes the five-member ring appears to be concerted with the departure of ethanol molecule, although the proton transfer from the nitrogen atom to oxygen atom is much more advanced in the transition state. Copyright © 2007 John Wiley & Sons, Ltd.
- Published
- 2007
188. Synthesis and Pharmacological Activity of a New Series of 1-(1H-Indol-4-yloxy)-3-(2-(2-methoxyphenoxy)ethylamino)propan-2-ol Analogs
- Author
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Marek, Bednarski, Monika, Otto, Magdalena, Dudek, Marcin, Kołaczkowski, Adam, Bucki, Agata, Siwek, Grażyna, Groszek, Elżbieta, Maziarz, Piotr, Wilk, and Jacek, Sapa
- Subjects
Models, Molecular ,Indoles ,Propanols ,Vasodilator Agents ,Blood Pressure ,Stereoisomerism ,Rats ,Radioligand Assay ,Structure-Activity Relationship ,Receptors, Adrenergic, alpha-1 ,Ethylamines ,Animals ,Receptors, Adrenergic, beta-1 ,Anti-Arrhythmia Agents ,Antihypertensive Agents - Abstract
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.
- Published
- 2015
189. The antidepressant-like activity of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one involves serotonergic 5-HT(1A) and 5-HT(2A/C) receptors activation
- Author
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Anna M. Waszkielewicz, Barbara Filipek, Anna Rapacz, Henryk Marona, Agnieszka Kij, Jacek Sapa, Adam Galuszka, Grzegorz Kazek, Adrian Olczyk, Agata Siwek, Karolina Pytka, and Maria Walczak
- Subjects
Male ,medicine.medical_specialty ,5-HT2A receptor ,medicine.drug_class ,Xanthones ,Ritanserin ,Pharmacology ,Motor Activity ,Serotonergic ,Piperazines ,Mice ,Internal medicine ,medicine ,Receptor, Serotonin, 5-HT2C ,Animals ,Receptor, Serotonin, 5-HT2A ,5-HT receptor ,Swimming ,Behavior, Animal ,Dose-Response Relationship, Drug ,Chemistry ,Depression ,Brain ,Serotonin 5-HT1 Receptor Agonists ,Receptor antagonist ,Tail suspension test ,Antidepressive Agents ,Disease Models, Animal ,Endocrinology ,Mechanism of action ,Xanthenes ,Rotarod Performance Test ,Receptor, Serotonin, 5-HT1A ,medicine.symptom ,Serotonin 5-HT2 Receptor Agonists ,Behavioural despair test ,medicine.drug - Abstract
Xanthone derivatives have been shown to posses many biological properties. Some of them act within the central nervous system and show neuroprotective or antidepressant like properties. Taking this into account we investigated antidepressant like activity in mice and the possible mechanism of action of 6-methoxy-2-[4-(2-methoxyphenyl)piperazin-1-yl]-9H-xanthen-9-one (HBK-11) - a new xanthone derivative. We demonstrated that HBK-11 produced antidepressant like effects in the forced swim test and tail suspension test, comparable to that of venlafaxine. The combined treatment with sub effective doses of HBK-11 and fluoxetine (but not reboxetine or bupropion) significantly reduced the immobility in the forced swim test. Moreover, the antidepressant like activity of HBK-11 in the aforementioned test was blocked by p-chlorophertylalanine, and significantly reduced by serotonergic $5-HT_{1A}$ receptor antagunist - WAY-1006335 and $5-HT_{2A/C}$ receptor antagonist - ritanserin. As none of the above treatments influenced the spontaneous locomotor activity, if can be concluded that HBK-11 mediates its activity through a serotonergic system, and its antidepressant like effect involves $5-HT_{1A}$ and $5-HT_{2A/C}$ receptor activation. Furthermore, at antidepressant like doses HBK-11 did not cause the mice to display locomotor deficits in rotarod or chimney rests. Considering the pharmacokinetic profile, HBK-11 demonstrated rapid absorption after i.p. administration, high clearance value, short terminal half-life, very high volume of distribution and incomplete bioavailabilily. The compound studied had good penetration into the brain tissue of mice. Since studied xanthone derivative seems to present interesting, untypical mechanism of antidepressant-like action i.e. $5-HT_{2A/C}$ receptor activation, it may have a potential in the treatment of depressive disorders, and surely requires further studies.
- Published
- 2015
190. Antiarrhythmic and α-Adrenoceptor Antagonistic Properties of Novel Arylpiperazine Derivatives of Pyrrolidin-2-one
- Author
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Paula, Zaręba, Magdalena, Dudek, Klaudia, Lustyk, Agata, Siwek, Gabriela, Starowicz, Marek, Bednarski, Leszek, Nowiński, Małgorzata, Zygmunt, Jacek, Sapa, Barbara, Malawska, and Katarzyna, Kulig
- Subjects
Male ,Epinephrine ,Molecular Structure ,Arrhythmias, Cardiac ,CHO Cells ,Transfection ,Piperazines ,Pyrrolidinones ,Disease Models, Animal ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,Heart Rate ,Drug Design ,Receptors, Adrenergic, alpha-1 ,Adrenergic alpha-1 Receptor Antagonists ,Animals ,Rats, Wistar ,Anti-Arrhythmia Agents ,Protein Binding - Abstract
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.
- Published
- 2015
191. Structure-activity relationships and molecular studies of novel arylpiperazinylalkyl purine-2,4-diones and purine-2,4,8-triones with antidepressant and anxiolytic-like activity
- Author
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Anna Partyka, Maciej Pawłowski, Andrzej J. Bojarski, Agata Siwek, Grzegorz Kazek, Grzegorz Satała, Marcin Kołaczkowski, Agnieszka Zagórska, Adam Bucki, and Anna Wesołowska
- Subjects
Models, Molecular ,Purine ,Stereochemistry ,medicine.drug_class ,Substituent ,Pyrimidinones ,Anxiolytic ,Piperazines ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dopamine receptor D2 ,Drug Discovery ,medicine ,Animals ,Receptor ,Piperazine ,Pharmacology ,Binding Sites ,Molecular Structure ,Organic Chemistry ,Dopaminergic ,General Medicine ,Combinatorial chemistry ,Antidepressive Agents ,Disease Models, Animal ,Anti-Anxiety Agents ,chemistry ,Purines ,Docking (molecular) ,Serotonin - Abstract
A novel series of arylpiperazinylalkyl purine-2,4-diones (4–27) and purine-2,4,8-triones (31–38) was synthesized and tested to evaluated their affinity for the serotoninergic (5-HT1A, 5-HT6, 5-HT7) and dopaminergic (D2) receptors. Compounds with purine-2,4-dione nucleus generally had affinity values higher than the corresponding purine-2,4,8-trione compounds. A spectrum of receptor activities was observed for compounds with a substituent at the 7-position of the imidazo[2,1-f]purine-2,4-dione system and some potent 5-HT1A (18, 25), 5-HT7 (14) and mixed 5-HT1A/5-HT7 (8, 9) receptor ligands with additional affinity for dopamine D2 receptors (15) has been identified. Moreover, docking studies proved that a substituent at the 7-position of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione could be essential for receptor affinity and selectivity, especially towards 5-HT1A and 5-HT7. The results of the preliminary pharmacological in vivo studies of selected derivatives of 1,3-dimethyl-(1H,8H)-imidazo[2,1-f]purine-2,4-dione, including 9 as a potential anxiolytic, 8 and 15 as potential antidepressants, and 18 and 25 as potential antidepressant and anxiolytic agents.
- Published
- 2015
192. Biofunctional studies of new 2-methoxyphenylpiperazine xanthone derivatives with α1-adrenolytic properties
- Author
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Leszek Nowiński, Karolina Pytka, Anna Rapacz, Szczepan Mogilski, Barbara Filipek, Natalia Szkaradek, Agata Siwek, Henryk Marona, and Jacek Sapa
- Subjects
Pharmacology ,Aorta ,Adrenergic receptor ,Chemistry ,Vas deferens ,Spleen ,General Medicine ,Small intestine ,medicine.anatomical_structure ,medicine.artery ,medicine ,Potency ,Selectivity ,Receptor - Abstract
Background The aim of this study was to assess the selectivity of the studied xanthone derivatives for α 1 -adrenoceptor subtypes (α 1A , α 1B , α 1D , α 1L ) in functional experiments in order to verify if they possess any selectivity for a distinct subtype of α 1 -adrenoceptor. Moreover, several pharmacological tests were carried out to assess whether they reveal other than α 1 -adrenoceptor blocking properties such as: antagonistic for 5-HT 2 receptors, vasorelaxant or spasmolytic. Methods The influence on α 1A -adrenoceptors was examined in biofunctional studies employing isolated rat vas deferens, on α 1B -adrenoceptors in guinea-pig spleen, on α 1D -adrenoceptors in rat aorta, and on α 1L -adrenoceptors in rabbit spleen. Affinity for 5-HT 2 receptors was measured in radioligand binding assay, whereas antagonistic potency for 5-HT 2 receptors was studied on isolated rat aorta. Vasorelaxant effect of tested compounds was assessed in functional study employing rat aorta, whereas direct spasmolytic activity was investigated using the isolated rabbit small intestine. Results The present study provides evidences that the tested 2-methoxyphenylpiperazine xanthone derivatives are non-selective α 1 -adrenoceptor blockers. However, at higher concentrations the direct spasmolytic effect could enhance their hypotensive activity. The obtained results indicate that the studied xanthones possessed weak calcium entry blocking activity, as well as antagonistic properties for 5-HT 2A receptors. Conclusions The results of the present study support the idea that the hypotensive activity of the studied compounds is related to their α 1 -adrenolytic properties.
- Published
- 2015
193. Novel 4-aryl-pyrido[1,2-c]pyrimidines with dual SSRI and 5-HT1A activity. Part 4
- Author
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Andrzej Chodkowski, Martyna Z. Wróbel, Jadwiga Turło, Jerzy Kleps, Agata Siwek, Gabriel Nowak, Mariusz Belka, Tomasz Bączek, Aleksander P. Mazurek, and Franciszek Herold
- Subjects
Pharmacology ,Structure-Activity Relationship ,Pyrimidines ,Dose-Response Relationship, Drug ,Molecular Structure ,Organic Chemistry ,Drug Discovery ,Receptor, Serotonin, 5-HT1A ,Humans ,General Medicine ,Selective Serotonin Reuptake Inhibitors - Abstract
This project describes the synthesis, pharmacological and pharmacodynamic tests on two series of novel derivatives of 2H-pyrido[1,2-c]pyrimidine with potential binary binding to 5-HT1A receptors and SSRI + serotonin transporters. The influence of piperidinyl-indole (8.1-8.7) and tetrahydropyridinyl-indole (8.8-8.32) residues and indole 5-position substituents (R3 = Br, Cl, F) present in the pharmacophore element of ligands on their binding to both molecular targets was tested. A considerable impact of piperidinyl-indole residue on binding to both targets was confirmed and compounds with a high binding affinity were identified: Ki 5-HT1A = 12.4 nM; Ki SERT = 15.6 nM 8.1; Ki 5-HT1A = 5.6 nM; Ki SERT = 20.7 nM 8.7, while the presence of a tetrahydropyridinyl-indole residue was found to reduce the affinity of ligands to 5-HT1AR. The presence of chlorine (R3) in this series resulted in a notable reduction in binding to both targets (5-HT1A and SERT). Selected compounds had their metabolic stability in a first-pass test (human liver microsomes, NADPH) determined in vitro, and R1 and R2 substituents present on the terminal residue of pyrido[1,2-c]pyrimidine were recognized as having an impact on stability.
- Published
- 2015
194. Antidepressant- and anxiolytic-like effects of new dual 5-HT_{1A} and 5-HT_{7} antagonists in animal models
- Author
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Barbara Mordyl, Adrian Olczyk, Karolina Pytka, Agata Siwek, Magdalena Jastrzębska-Więsek, Anna M. Waszkielewicz, Jacek Sapa, Adam Galuszka, Anna Partyka, Barbara Filipek, Marian J. Blachuta, Henryk Marona, Anna Wesołowska, Anna Rapacz, Grzegorz Kazek, and Monika Głuch-Lutwin
- Subjects
Male ,medicine.medical_specialty ,Elevated plus maze ,Phenylpiperazine ,Pharmacology ,Anxiety ,Serotonergic ,Imipramine ,chemistry.chemical_compound ,Mice ,Dopamine receptor D2 ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,5-HT receptor ,Multidisciplinary ,Depression ,Rats ,Endocrinology ,chemistry ,Receptors, Serotonin ,Models, Animal ,Receptor, Serotonin, 5-HT1A ,Serotonin Antagonists ,Diazepam ,Locomotion ,Behavioural despair test ,medicine.drug ,Research Article - Abstract
The aim of this study was to further characterize pharmacological properties of two phenylpiperazine derivatives: 1-{2-[2-(2,6-dimethlphenoxy)ethoxy]ethyl}-4-(2-methoxyphenyl)piperazynine hydrochloride (HBK-14) and 2-[2-(2-chloro-6-methylphenoxy)ethoxy]ethyl-4-(2- methoxyphenyl)piperazynine dihydrochloride (HBK-15) in radioligand binding and functional in vitro assays as well as in vivo models. Antidepressant-like properties were investigated in the forced swim test (FST) in mice and rats. Anxiolytic-like activity was evaluated in the four-plate test in mice and elevated plus maze test (EPM) in rats. Imipramine and escitalopram were used as reference drugs in the FST, and diazepam was used as a standard anxiolytic drug in animal models of anxiety. Our results indicate that HBK-14 and HBK-15 possess high or moderate affinity for serotonergic 5-HT2, adrenergic α1, and dopaminergic D2 receptors as well as being full 5-HT1A and 5-HT7 receptor antagonists. We also present their potent antidepressant-like activity (HBK-14—FST mice: 2.5 and 5 mg/kg; FST rats: 5 mg/kg) and (HBK-15—FST mice: 1.25, 2.5 and 5 mg/kg; FST rats: 1.25 and 2.5 mg/kg). We show that HBK-14 (four-plate test: 2.5 and 5 mg/kg; EPM: 2.5 mg/kg) and HBK-15 (four-plate test: 2.5 and 5 mg/kg; EPM: 5 mg/kg) possess anxiolytic-like properties. Among the two, HBK-15 has stronger antidepressant-like properties, and HBK-14 displays greater anxiolytic-like activity. Lastly, we demonstrate the involvement of serotonergic system, particularly 5-HT1A receptor, in the antidepressant- and anxiolytic-like actions of investigated compounds.
- Published
- 2015
195. Evaluation of the role of NMDA receptor function in antidepressant-like activity. A new study with citalopram and fluoxetine in the forced swim test in mice
- Author
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Bernadeta Szewczyk, Małgorzata Wolak, Gabriel Nowak, Ewa Poleszak, Anita Rutkowska, Katarzyna Młyniec, Beata Bystrowska, Andrzej Moniczewski, and Agata Siwek
- Subjects
Male ,CGP-37849 ,Drug Evaluation, Preclinical ,Pharmacology ,Citalopram ,Receptors, N-Methyl-D-Aspartate ,chemistry.chemical_compound ,Mice ,Fluoxetine ,medicine ,Animals ,Swimming ,business.industry ,Depression ,Glutamate receptor ,Antagonist ,General Medicine ,Antidepressive Agents ,chemistry ,2-Amino-5-phosphonovalerate ,Antidepressant ,NMDA receptor ,Antidepressive Agents, Second-Generation ,business ,Behavioural despair test ,medicine.drug - Abstract
Background The NMDA/glutamate receptors are involved in the mechanism of antidepressant activity. Methods The present study was designed to investigate the effect of NMDA receptor ligands (agonists and antagonists of glutamate sites) on the antidepressant-like activity of selective serotonin reuptake inhibitors (SSRIs), citalopram and fluoxetine, in the forced swim test in mice. Results The antidepressant activity (reduction in immobility time) of citalopram but not of fluoxetine was antagonized by N-methyl- d -aspartate acid and enhanced by CGP37849 (antagonist of the NMDA receptor). Conclusions The present literature data indicate that the antidepressant-like activity of conventional antidepressants is generally affected by the NMDA receptor, although by modulation from different sites of the complex. Thus, it supports the issue of the ability of NMDA receptor antagonists to enhance the antidepressant action in human depression.
- Published
- 2014
196. Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia
- Author
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Grzegorz Kazek, Anna Partyka, Przemyslaw Bienkowski, Maciej Pawłowski, Monika Marcinkowska, Paweł Mierzejewski, Magdalena Jastrzębska-Więsek, Agata Siwek, Anna Wasik, Adam Bucki, Marcin Kołaczkowski, Anna Wesołowska, and Joanna Śniecikowska
- Subjects
Male ,Models, Molecular ,Indoles ,Pharmacology ,Quinolones ,Ligands ,Partial agonist ,Piperazines ,Structure-Activity Relationship ,Dopamine receptor D2 ,Drug Discovery ,Animals ,Humans ,Rats, Wistar ,5-HT receptor ,Swimming ,Dose-Response Relationship, Drug ,Molecular Structure ,Chemistry ,Receptors, Dopamine D2 ,Organic Chemistry ,Antagonist ,General Medicine ,Muscarinic acetylcholine receptor M1 ,Rats ,Drug Partial Agonism ,Docking (molecular) ,Receptors, Serotonin ,Benzamides ,5-HT6 receptor ,Dementia ,Pharmacophore - Abstract
We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying in vitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits.
- Published
- 2014
197. Biofunctional studies of new 2-methoxyphenylpiperazine xanthone derivatives with α₁-adrenolytic properties
- Author
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Anna, Rapacz, Jacek, Sapa, Leszek, Nowiński, Szczepan, Mogilski, Karolina, Pytka, Barbara, Filipek, Agata, Siwek, Natalia, Szkaradek, and Henryk, Marona
- Subjects
Male ,Dose-Response Relationship, Drug ,Xanthones ,Guinea Pigs ,Piperazines ,Potassium Chloride ,Rats ,Radioligand Assay ,Ileum ,Adrenergic alpha-1 Receptor Antagonists ,Animals ,Humans ,Calcium Channels ,Rabbits ,Receptors, Serotonin, 5-HT2 ,Aorta ,Spleen - Abstract
The aim of this study was to assess the selectivity of the studied xanthone derivatives for α1-adrenoceptor subtypes (α1A, α1B, α1D, α1L) in functional experiments in order to verify if they possess any selectivity for a distinct subtype of α1-adrenoceptor. Moreover, several pharmacological tests were carried out to assess whether they reveal other than α1-adrenoceptor blocking properties such as: antagonistic for 5-HT2 receptors, vasorelaxant or spasmolytic.The influence on α1A-adrenoceptors was examined in biofunctional studies employing isolated rat vas deferens, on α1B-adrenoceptors in guinea-pig spleen, on α1D-adrenoceptors in rat aorta, and on α1L-adrenoceptors in rabbit spleen. Affinity for 5-HT2 receptors was measured in radioligand binding assay, whereas antagonistic potency for 5-HT2 receptors was studied on isolated rat aorta. Vasorelaxant effect of tested compounds was assessed in functional study employing rat aorta, whereas direct spasmolytic activity was investigated using the isolated rabbit small intestine.The present study provides evidences that the tested 2-methoxyphenylpiperazine xanthone derivatives are non-selective α1-adrenoceptor blockers. However, at higher concentrations the direct spasmolytic effect could enhance their hypotensive activity. The obtained results indicate that the studied xanthones possessed weak calcium entry blocking activity, as well as antagonistic properties for 5-HT2A receptors.The results of the present study support the idea that the hypotensive activity of the studied compounds is related to their α1-adrenolytic properties.
- Published
- 2014
198. Novel arylsulfonamide derivatives with 5-HT₆/5-HT₇ receptor antagonism targeting behavioral and psychological symptoms of dementia
- Author
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Marcin, Kołaczkowski, Monika, Marcinkowska, Adam, Bucki, Maciej, Pawłowski, Katarzyna, Mitka, Jolanta, Jaśkowska, Piotr, Kowalski, Grzegorz, Kazek, Agata, Siwek, Anna, Wasik, Anna, Wesołowska, Paweł, Mierzejewski, and Przemyslaw, Bienkowski
- Subjects
Male ,Models, Molecular ,Benzoxazoles ,Catalepsy ,Sulfonamides ,CHO Cells ,Motor Activity ,Antidepressive Agents ,Dopamine D2 Receptor Antagonists ,Radioligand Assay ,Structure-Activity Relationship ,Cricetulus ,HEK293 Cells ,Receptors, Serotonin ,Avoidance Learning ,Animals ,Humans ,Dementia ,Serotonin Antagonists ,Rats, Wistar ,Antipsychotic Agents - Abstract
In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design to obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) and D2 receptors, without interacting with M1 receptors and hERG channels. In vitro studies confirmed their antagonism of 5-HT(7/2A) and D2 receptors and weak interactions with key antitargets (M1R and hERG) associated with side effects. Marked 5-HT6 receptor affinities were also observed, notably for 6-fluoro-3-(piperidin-4-yl)-1,2-benzoxazole derivatives connected by a 3-4 unit alkyl linker with mono- or bicyclic, lipophilic arylsulfonamide moieties. N-[4-[4-(6-Fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]butyl]benzothiophene-2-sulfonamide (72) was characterized in vitro on 14 targets and antitargets. It displayed dual blockade of 5-HT6 and D2 receptors and negligible interactions at hERG and M1 receptors. Unlike reference antipsychotics, 72 displayed marked antipsychotic and antidepressant activity in rats after oral administration, in the absence of cognitive or motor impairment. This profile is particularly attractive when targeting a fragile, elderly BPSD patient population.
- Published
- 2014
199. Pharmacological evaluation of the anxiolytic-like effects of EMD 386088, a partial 5-HT6 receptor agonist, in the rat elevated plus-maze and Vogel conflict tests
- Author
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Anna Wasik, Monika Kubacka, Marcin Kołaczkowski, Anna Partyka, Magdalena Jastrzębska-Więsek, Agata Siwek, Anna Wesołowska, and Szczepan Mogilski
- Subjects
Agonist ,Male ,Pain Threshold ,Elevated plus maze ,medicine.medical_specialty ,Indoles ,medicine.drug_class ,Pyridines ,Guinea Pigs ,Drinking Behavior ,Pharmacology ,Anxiety ,Neuropsychological Tests ,Conflict, Psychological ,Cellular and Molecular Neuroscience ,chemistry.chemical_compound ,Random Allocation ,Internal medicine ,medicine ,Animals ,Rats, Wistar ,Maze Learning ,Dose-Response Relationship, Drug ,GABAA receptor ,Receptor antagonist ,Receptors, GABA-A ,Serotonin Receptor Agonists ,Endocrinology ,EMD-386088 ,chemistry ,Mechanism of action ,Anti-Anxiety Agents ,Flumazenil ,Receptors, Serotonin ,5-HT6 receptor ,Exploratory Behavior ,medicine.symptom ,Receptors, Serotonin, 5-HT3 ,medicine.drug - Abstract
The 5-HT6 is one of the most recent additions to the 5-HT receptor family. Its pharmacological profile and anatomical distribution is suggestive of a putative role in mood disorders. Most of preclinical evidence suggests an anxiolytic-like action of 5-HT6 receptor antagonists. Evaluation the anxiolytic-like effects of EMD 386088, a partial 5-HT6receptor agonist, and its putative mechanism of action in rats. EMD 386088, administered intraperitoneally at a dose of 2.5 mg/kg evoked specific anxiolytic-like activity in the automated version of the conflict drinking Vogel and the elevated plus-maze tests visible by increasing all parameters indicating a potential anti-anxiety effect. Its activity was blocked by the selective 5-HT6 receptor antagonist SB 271046, but not by the selective GABAA/benzodiazepine receptor antagonist flumazenil. EMD 386088 did not intensify an anxiolytic-like effect produced by diazepam in the elevated plus-maze test. These findings suggest that EMD 386088, a 5-HT6 receptor agonist, produces anxiolytic-like activity after systemic administration which may result from direct stimulation of 5-HT6 receptors.
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- 2014
200. Identification of novel serotonin transporter compounds by virtual Screening
- Author
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Rafał Kurczab, Zdzisław Chilmonczyk, Gabriel Nowak, Ingebrigt Sylte, Kurt Kristiansen, Andrzej J. Bojarski, Mari Gabrielsen, Aina Westrheim Ravna, Ruben Abagyan, Małgorzata Wolak, Irina Kufareva, and Agata Siwek
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Synaptic cleft ,Databases, Pharmaceutical ,General Chemical Engineering ,In silico ,Medicinal & Biomolecular Chemistry ,Library and Information Sciences ,Pharmacology ,Serotonergic ,Article ,03 medical and health sciences ,Databases ,Medicinal and Biomolecular Chemistry ,0302 clinical medicine ,Theoretical and Computational Chemistry ,Drug Discovery ,Humans ,Serotonin transporter ,030304 developmental biology ,Serotonin Plasma Membrane Transport Proteins ,0303 health sciences ,Virtual screening ,Psychotropic Drugs ,Binding Sites ,biology ,Drug discovery ,Neurosciences ,Computation Theory and Mathematics ,General Chemistry ,3. Good health ,Computer Science Applications ,Molecular Docking Simulation ,Biochemistry ,Docking (molecular) ,Pharmaceutical ,biology.protein ,Pharmacophore ,030217 neurology & neurosurgery ,Protein Binding - Abstract
The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) plays an essential role in the termination of serotonergic neurotransmission by removing 5-HT from the synaptic cleft into the presynaptic neuron. It is also of pharmacological importance being targeted by antidepressants and psychostimulant drugs. Here, five commercial databases containing approximately 3.24 million drug-like compounds have been screened using a combination of two-dimensional (2D) fingerprint-based and three-dimensional (3D) pharmacophore-based screening and flexible docking into multiple conformations of the binding pocket detected in an outward-open SERT homology model. Following virtual screening (VS), selected compounds were evaluated using in vitro screening and full binding assays and an in silico hit-to-lead (H2L) screening was performed to obtain analogues of the identified compounds. Using this multistep VS/H2L approach, 74 active compounds, 46 of which had K(i) values of ≤1000 nM, belonging to 16 structural classes, have been identified, and multiple compounds share no structural resemblance with known SERT binders.
- Published
- 2014
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