A5085355095- Receptor Mechanisms and Signaling
- Synthesis and Biological Evaluation
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Neurotransmitter Receptor Influence on Behavior
- Neuroscience and Neuropharmacology Research
- Phenothiazines and Benzothiazines Synthesis and Activities
- Pharmacological Receptor Mechanisms and Effects
- Chemical Synthesis and Analysis
- Chemical synthesis and alkaloids
- Click Chemistry and Applications
- Chemical Reaction Mechanisms
- Computational Drug Discovery Methods
- Synthesis and Characterization of Heterocyclic Compounds
- Synthesis and Reactions of Organic Compounds
- Synthesis of heterocyclic compounds
- Cholinesterase and Neurodegenerative Diseases
- Adenosine and Purinergic Signaling
- Synthesis and Reactivity of Heterocycles
- Coordination Chemistry and Organometallics
- Cyclopropane Reaction Mechanisms
- Fluorine in Organic Chemistry
- Phosphodiesterase function and regulation
- Nicotinic Acetylcholine Receptors Study
- Treatment of Major Depression
Maj Institute of Pharmacology
2016-2025
Polish Academy of Sciences
2016-2025
Polish Academy of Learning
2016-2024
Medicina
2013-2022
Institute of Pharmacology
2015-2018
Cracow University of Technology
2018
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...
Modulators of the serotonin 5-HT6 receptor (5-HT6R) offer a promising strategy for treatment cognitive deficits that are associated with dementia and Alzheimer's disease. Herein, we report design, synthesis, characterization novel class 5-HT6R antagonists is based on 1H-pyrrolo[3,2-c]quinoline core. The most active compounds exhibited comparable binding affinity to reference compound, SB-742457, markedly improved selectivity. Lead optimization led identification...
Abstract Fragment-based drug design has introduced a bottom-up process for development, with improved sampling of chemical space and increased effectiveness in early discovery. Here, we combine the use pharmacophores, most general concept representing drug-target interactions theory protein hotspots, to develop protocol fragment libraries. The SpotXplorer approach compiles small libraries that maximize coverage experimentally confirmed binding pharmacophores at preferred hotspots. efficiency...
A series of new derivatives N-(2-methoxyphenyl)piperazine have been synthesized for their affinity toward serotonergic receptors and potential antidepressant-like activity. They evaluated 5-HT1A , 5-HT6 5-HT7 as well in vivo the tail suspension, locomotor activity, motor co-ordination tests. All tested compounds proved very good affinities receptors. The most promising compound was 1-[(2-chloro-6-methylphenoxy)ethoxyethyl]-4-(2-methoxyphenyl)piperazine hydrochloride, exhibiting Ki <1 nm...
Among serotonin receptors, the 5-HT6 subtype is most controversial and least known in field of molecular mechanisms. The 5-HT6R ligands can be pivotal for innovative treatment cognitive impairment, but none has reached pharmacological market, predominantly, due to insufficient “druglikeness” properties. Recently, 1,3,5-triazine-piperazine derivatives were identified as a new chemical family potent ligands. For active triazine agents found (1–4), wider binding profile comprehensive vitro...
Significant amounts of enolase—a cytosolic enzyme involved in the glycolysis pathway—are exposed on cell surface Candida yeast. It has been hypothesized that this enolase form contributes to infection-related phenomena such as fungal adhesion human tissues, and activation fibrinolysis extracellular matrix degradation. The aim present study was characterize, structural terms, protein-protein interactions underlying these moonlighting functions enolase. tight binding vitronectin, fibronectin...
Abstract INTRODUCTION Hyperphosphorylation and aggregation of the microtubule‐associated protein tau cause development tauopathies, such as Alzheimer's disease frontotemporal dementia (FTD). We recently uncovered a causal link between constitutive serotonin receptor 7 (5‐HT7R) activity pathological aggregation. Here, we evaluated 5‐HT7R inverse agonists novel drugs in treatment tauopathies. METHODS Based on structural homology, screened multiple approved for their agonism toward 5‐HT7R....
Since the year 1993, when 5-HT7 receptor (5-HT7 R) was discovered, there is no selective R ligand introduced to pharmaceutical market. One out of main reasons disqualifying ligands weak drugability properties, including metabolic instability or low permeability. This study focused on search a lead compound by "drug-likeness" estimation first series and potent among 5-(4-fluorophenyl)-3-(2-hydroxy-3-(4-aryl-piperazin-1-yl)propyl)-5-methylimidazolidine-2,4-dione derivatives (11-16). The most...
A series of N1-azinylsulfonyl-3-(1,2,3,6,tetrahyrdopyridin-4-yl)-1H-indole derivatives was designed to obtain highly potent 5-HT6 receptor ligands. The study allowed for the identification 25 (4-{[5-methoxy-3-(1,2,3,6-tetrahydropyridin-4-yl)-1H-indol-1-yl]sulfonyl}isoquinoline), a and selective antagonist. selected compound, evaluated in vivo novel object recognition (NOR) forced swim (FST) tests rats, demonstrating distinct pro-cognitive antidepressant-like properties (MED = 1 mg/kg 0.1...
Herein, we describe the design, synthesis, and biological evaluation of 15
A virtual screening campaign aimed at finding structurally new compounds active 5-HT6R provided a set of candidates. Among those, one structure, 4-(5-{[(2-{5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)amino]methyl}furan-2-yl)phenol (1, Ki = 91 nM), was selected as hit for further optimization. As expected, the chemical scaffold compound significantly different from all serotonin receptor ligands published to date. Synthetic efforts, supported by molecular modelling, 43 representing...
A computational approach combining a structure-activity relationship library of halogenated and the corresponding unsubstituted ligands (called XSAR) with QM-based molecular docking binding free energy calculations was used to search for amino acids frequently targeted by halogen bonding (hot spots) in 5-HT7R as case study. The procedure identified two sets hot spots, extracellular (D2.65, T2.64, E7.35) transmembrane (C3.36, T5.39, S5.42), which were further verified synthesized...