A5088814932- Receptor Mechanisms and Signaling
- X-ray Diffraction in Crystallography
- Crystallization and Solubility Studies
- Cholinesterase and Neurodegenerative Diseases
- Phenothiazines and Benzothiazines Synthesis and Activities
- Phosphodiesterase function and regulation
- Vanadium and Halogenation Chemistry
- Neurotransmitter Receptor Influence on Behavior
- Synthesis and Biological Evaluation
- Pharmacological Receptor Mechanisms and Effects
- Computational Drug Discovery Methods
- Metal-Catalyzed Oxygenation Mechanisms
- Neuroscience and Neuropharmacology Research
- Neuropeptides and Animal Physiology
- Tryptophan and brain disorders
- Synthesis and biological activity
- Bipolar Disorder and Treatment
- Alzheimer's disease research and treatments
- Synthesis and Characterization of Heterocyclic Compounds
- Chemical Reaction Mechanisms
- Chemical synthesis and alkaloids
- Metal complexes synthesis and properties
- Treatment of Major Depression
- Chemical Synthesis and Analysis
- Natural Antidiabetic Agents Studies
Jagiellonian University
2016-2025
Pharmac
2018
Krakow Cardiovascular Research Institute
2017
Alzheimer's disease (AD) has a complex and not-fully-understood etiology. Recently, the serotonin receptor 5-HT6 emerged as promising target for AD treatment; thus, here new series of 5-HT6R ligands with 1,3,5-triazine core selenoether linkers was explored. Among them, 2-naphthyl derivatives exhibited strong affinity selectivity over 5-HT1AR (13–15), 5-HT7R (14 15), 5-HT2AR (13). Compound 15 displayed high other central nervous system receptors low risk cardio-, hepato-, nephrotoxicity no...
Alzheimer's disease (AD) is a major public health problem, which due to its increasing prevalence and lack of effective therapy or diagnostics. The complexity the AD pathomechanism requires complex treatment, e.g. multifunctional ligands targeting both causes symptoms disease. Here, we present new multitarget-directed combining pharmacophore fragments that provide blockade serotonin 5-HT6 receptors, acetyl/butyrylcholinesterase inhibition, amyloid β antiaggregation activity. Compound 12 has...
Carbon dots (CDs) are carbon-based zero-dimensional nanomaterials that can be prepared from a number of organic precursors. In this research, they using fat-free UHT cow milk through the hydrothermal method. FTIR analysis shows C=O and C-H bond presence, as well nitrogen-based like C-N, C=N -NH
Among serotonin receptors, the 5-HT6 subtype is an important protein target and its ligands may play a key role in innovative treatment of cognitive disorders. This study aimed to extend body preclinical research on two naphthyl-derived methylpiperazine-1,3,5-triazine analogues with thioether (WA-22) or Se-ether (PPK-32) linkers, newly described compounds having high affinity selectivity for receptors drug-like parameters vitro. Thus, crystallography-supported deeper insight into their...
The aim of this study was to further characterize pharmacological properties 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 functional vitro assays as well vivo models. Antidepressant-like were investigated the forced swim test (FST) mice rats. Anxiolytic-like activity evaluated...
New tritarget small molecules combining Ca2+ channels blockade, cholinesterase, and H3 receptor inhibition were obtained by multicomponent synthesis. Compound 3p has been identified as a very promising lead, showing good blockade activity (IC50 = 21 ± 1 μM), potent affinity against hH3R (Ki 565 62 nM), moderate but selective hBuChE 7.83 0.10 strong antioxidant power (3.6 TE), ability to restore cognitive impairment induced lipopolysaccharide.
The search for drugs with anorectic activity, acting within the adrenergic system has attracted interest of researchers. Partial α2-adrenoceptor agonists might offer potential effective and safe treatment obesity. We compared effectiveness safety ligands in reducing body mass. also analyzed if antagonist partial α2-adrenoceptor––yohimbine guanfacine––act similarly, determined which course action is connected activity. tested intrinsic activity effect on lipolysis these compounds cell...
Studies suggest that the blockade of 5-HT1A, 5-HT7, and 5-HT3 receptor may increase speed antidepressant response. 1-[(2,6-Dimethylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride (HBK-14) 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine (HBK-15), dual 5-HT1A 5-HT7 antagonists, showed significant antidepressant- anxiolytic-like properties in our previous tests rodents. In this study, we aimed to investigate their potential using mouse model...
Janusz Szklarzewicz*a, Anna Jurowskaa, Maciej Hodorowicza, Ryszard Grybośa, Krzysztof Kruczałaa, Monika Głuch-Lutwinb & Grzegorz Kazekba aFaculty of Chemistry, Jagiellonian University, Kraków, Poland; b bFaculty Pharmacy, University Medical College, Poland
The lack of an effective treatment makes Alzheimer's disease a serious healthcare problem and challenge for medicinal chemists. Herein we report interdisciplinary research on novel multifunctional ligands targeting proteins processes involved in the development disease: BuChE, 5-HT6 receptors β-amyloid aggregation. Structure-activity relationship analyses supported by crystallography docking studies led to identification fused-type ligand 50, with remarkable balanced potencies against BuChE...
Alzheimer's disease is becoming a growing problem increasing at tremendous rate. Serotonin 5-HT6 receptors appear to be particularly attractive target from therapeutic perspective, due their involvement not only in cognitive processes, but also depression and psychosis. In this work, we present the synthesis broad biological characterization of new series 18 compounds with unique 1,3,5-triazine backbone, as potent receptor ligands. The main aim research compare activity newly synthesized...
GSK-3β, IKK-β, and ROCK-1 kinases are implicated in the pathomechanism of Alzheimer’s disease due to their involvement misfolding accumulation amyloid β (Aβ) tau proteins, as well inflammatory processes. Among these kinases, GSK-3β plays most crucial role. In this study, we present compound 62, a novel, remarkably potent, competitive inhibitor (IC50 = 8 nM, Ki 2 nM) that also exhibits additional inhibitory activity 2.3 µM) demonstrates anti-inflammatory neuroprotective properties. Compound...
The most troublesome aspects of behavioral and psychological symptoms dementia (BPSD) are nowadays addressed by antidepressant, anxiolytic, antipsychotic drugs, often administered off-label. Considering their modest effectiveness in patients, the increased risk adverse events cognitive decline, there is an unmet need for well-tolerated effective therapy BPSD. We designed synthesized multifunctional ligands characterized vitro as high-affinity partial agonists D2R, antagonists 5-HT6R,...
Histamine H4 receptor (H4R) offers a great potential for new therapeutic strategies the treatment of inflammation-based diseases. The aim this study is to present pharmacological profile two recently synthesized ligands H4R with particular reference their anti-inflammatory and analgesic activity.We used mice rats in vivo tests. We also murine RAW 264.7 cells isolated guinea-pig ileum vitro test.In tests, animals were pre-treated increasing doses investigated compounds (12.5, 25 50 mg/kg)...
Novel 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were designed as "biased agonists" of serotonin 5-HT1A receptors. The compounds tested in signal transduction assays (ERK1/2 phosphorylation, cAMP inhibition, Ca2+ mobilization, and β-arrestin recruitment) which identified ERK1/2 phosphorylation-preferring aryloxyethyl derivatives. novel series showed high receptor affinity, >1000-fold selectivity versus noradrenergic α1, dopamine D2, 5-HT2A, histamine H1, muscarinic M1 receptors,...
The present study aimed to design and synthesize a new series of hybrid compounds with pyrrolidine-2,5-dione thiophene rings in the structure as potential anticonvulsant antinociceptive agents. For this purpose, we obtained evaluated their activity animal models epilepsy (maximal electroshock (MES), psychomotor (6 Hz), subcutaneous pentylenetetrazole (scPTZ) seizure tests). To determine mechanism action most active (3, 4, 6, 9), influence on voltage-gated sodium calcium channels well GABA...
Multifunctional ligands as an essential variant of polypharmacology are promising candidates for the treatment multi-factorial diseases like Alzheimer's disease. Based on clinical evidence and following paradigm multifunctional we have rationally designed synthesized a series compounds targeting processes involved in development The biological evaluation led to discovery two with favorable pharmacological characteristics ADMET profile. Compounds 17 35 5-HT6R antagonists (Ki = 13 nM Ki 15...
In the pathogenesis of Alzheimer's disease, overexpression glycogen synthase kinase-3β (GSK-3β) stands out due to its multifaced nature, as it contributes promotion amyloid β and tau protein accumulation, well neuroinflammatory processes. Therefore, in present study, we have designed, synthesized, evaluated a new series GSK-3β inhibitors based on N-(pyridin-2-yl)cyclopropanecarboxamide scaffold. We identified compound 36, demonstrating an IC50 70 nM against GSK-3β. Subsequently, through...
A series of 2-fluoro and 3-trifluoromethylphenylpiperazinylalkyl derivatives 1H-imidazo[2,1-f]purine-2,4(3H,8H)-dione (4-21) were synthesized evaluated for their serotonin (5-HT1A/5-HT7) receptor affinity phosphodiesterase (PDE4B PDE10A) inhibitor activity. The study enabled the identification potent 5-HT1A, 5-HT7 mixed 5-HT1A/5-HT7 ligands with weak inhibitory potencies PDE4B PDE10A. tests have been completed determination lipophilicity metabolic stability using micellar electrokinetic...