A5026614694- Computational Drug Discovery Methods
- Neuroscience and Neuropharmacology Research
- Cholinesterase and Neurodegenerative Diseases
- Receptor Mechanisms and Signaling
- Analytical Chemistry and Chromatography
- Pharmacological Receptor Mechanisms and Effects
- Phosphodiesterase function and regulation
- GABA and Rice Research
- Chemical synthesis and alkaloids
- Pesticide Exposure and Toxicity
- Alzheimer's disease research and treatments
- Molecular Sensors and Ion Detection
- Chemical Synthesis and Analysis
- Neurotransmitter Receptor Influence on Behavior
- Cell Image Analysis Techniques
- Microtubule and mitosis dynamics
- Phenothiazines and Benzothiazines Synthesis and Activities
- Chemical Reactions and Isotopes
- Lipid Membrane Structure and Behavior
- Pharmacological Effects of Natural Compounds
- Low-power high-performance VLSI design
- Click Chemistry and Applications
- Environmental Toxicology and Ecotoxicology
- Analytical Methods in Pharmaceuticals
- Radio Frequency Integrated Circuit Design
Jagiellonian University
2018-2024
γ-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the nervous system. It plays crucial role many physiological processes. Upon release from presynaptic element, it removed synaptic cleft by reuptake due to action of GABA transporters (GATs). GATs belong large SLC6 protein family whose characteristic feature sodium-dependent relocation neurotransmitters through cell membrane. are characterized contexts, but their spatial structure not fully known. They divided into four...
Alzheimer's disease (AD) is a progressive neurodegenerative brain disease. Thus, drugs including donepezil, rivastigmine, and galantamine are not entirely effective in the treatment of this multifactorial The present study evaluates eight derivatives (3a-3h) as candidates with stronger anti-AD potential but less side effects. Reactive oxygen species (ROS) assays were used to assess oxidative stress which involve neurodegeneration. neuroprotective properties 3e against done three experiments...
Alzheimer's disease (AD) is a global health problem in the medical sector that will increase over time. The limited treatment of AD leads to search for new clinical candidate. Considering multifactorial nature AD, strategy targeting number regulatory proteins involved development an effective approach. Here, we present discovery multi-target-directed ligands (MTDLs), purposely designed as GABA transporter (GAT) inhibitors, successfully provide inhibitory activity against...
The norepinephrine transporter (NET) is one of the monoamine transporters. Its X-ray crystal structure has not been obtained yet. Inhibitors human NET (hNET) play a major role in treatment many central and peripheral nervous system diseases. In this study, we focused on spatial constructed by homology modeling Drosophila melanogaster dopamine templates. We further examined molecular construction primary binding pocket (S1) together with secondary site (S2) extracellular loop 4 (EL4). next...
Kainate receptors belong to the family of glutamate ion channels, which are responsible for majority rapid excitatory synaptic transmission in central nervous system. The therapeutic potential kainate is still poorly understood, also due lack potent and subunit-selective pharmacological tools. In search selective ligands GluK3 receptor subtype, a series quinoxaline-2,3-dione analogues was synthesized pharmacologically characterized at selected recombinant ionotropic receptors. Among them,...
Here we report the two-step synthesis of 8 new cyclopentaquinoline derivatives as modifications tetrahydroacridine structure. Next, biological assessment each them was performed. Based on obtained results identified 6-chloro-N-[2-(2,3-dihydro-1H-cyclopenta[b]quinolin-9-ylamino)-hexyl]]-nicotinamide hydrochloride (3e) most promising compound with inhibitory potencies against EeAChE and EqBuChE in low nanomolar level 67 153 nM, respectively. Moreover, 3e is non-hepatotoxic, able to inhibit...
γ-Aminobutyric acid transporters are responsible for regulating the GABA level in synaptic cleft. In this way, they affect GABA-ergic transmission which is important proper functioning of central nervous system. The exact structure still unknown, hinders design new, potent and selective inhibitors. For these reasons, we decided to create models all types human gamma-aminobutyric transporters. They were built based on crystal structures related proteins from SLC6 family using homology...
Abstract Lipophilicity is a physicochemical parameter well known as decisive factor for predicting the successful development of drug. Thus, balance between potency and properties during medicinal chemistry optimization needed. In this study, lipophilicity isoindole-1,3(2 H )-dione derivatives designed phosphodiesterase 10A (PDE10A) inhibitors was determined by chromatographic [reversed-phase thin-layer chromatography (RP-TLC) ultra-performance liquid chromatography/mass spectrometry...
Inhibitory neurotransmission mediated by γ-aminobutyric acid (GABA) plays an important role in maintaining body homeostasis. Disturbances GABA signaling are implicated a multitude of neurologic and psychiatric conditions, including epilepsy, ischemia, anxiety, depression, insomnia, mood disorders. Clinically relevant increases neurotransmitter level can be achieved inhibition its uptake into presynaptic neurons surrounding glial cells, driven transporters (GAT1, BGT1, GAT2, GAT3). Herein, we...
A series of new tetrahydroacridine and 3,5-dichlorobenzoic acid hybrids with different spacers were designed, synthesized, evaluated for their ability to inhibit both cholinesterase enzymes. Compounds 3a, 3b, 3f, 3g exhibited selective butyrylcholinesterase (EqBuChE) inhibition IC50 values ranging from 24 607 nM. Among them, compound 3b was the most active (IC50 = nM). Additionally, 3c EeAChE 25 nM EqBuChE 123 nM) displayed dual inhibitory activity against acetylcholinesterase (AChE). Active...
Poisoning with organophosphorus compounds used as pesticides or misused chemical weapons remains a serious threat to human health and life. Their toxic effects result from irreversible blockade of the enzymes acetylcholinesterase butyrylcholinesterase, which causes overstimulation cholinergic system often leads injury death. Treatment poisoning involves, among other strategies, administration oxime compounds. Oximes reactivate cholinesterases by breaking covalent bond between serine residue...
Neuropathic pain resistance to pharmacotherapy has encouraged researchers develop effective therapies for its treatment. γ-Aminobutyric acid (GABA) transporters 1 and 4 (mGAT1 mGAT4) have been increasingly recognized as promising drug targets neuropathic (NP) associated with imbalances in inhibitory neurotransmission. In this context, we designed synthesized new functionalized amino acids inhibitors of GABA uptake assessed their activities toward all four mouse GAT subtypes (mGAT1–4)....
Glycine transporters are interesting therapeutic targets as they play significant roles in glycinergic and glutamatergic systems. The search for new selective inhibitors of particular types glycine (GlyT-1 GlyT-2) with beneficial kinetics is hampered by limited knowledge about the spatial structure these proteins. In this study, a pool homology models GlyT-1 GlyT-2 different conformational states was constructed using crystal structures related from SLC6 family recently revealed inward-open...
The pyridinium-2-carbaldoximes with quinolinium carboxamide moiety were designed and synthesised as cholinesterase reactivators. prepared compounds showed intermediate-to-high inhibition of both cholinesterases when compared to standard oximes. Their reactivation ability was evaluated in vitro on human recombinant acetylcholinesterase (hrAChE) butyrylcholinesterase (hrBChE) inhibited by nerve agent surrogates (NIMP, NEMP, NEDPA) or paraoxon. In the screening, one compound able reactivate...
The recently obtained cryo-electron microscopy structure (PDB code: 7SK2) of the human γ-aminobutyric acid transporter type 1 (hGAT-1) in complex with antiepileptic drug, tiagabine, revealed a rather unexpected binding mode for this inhibitor an inward-open state transporter. simultaneously released crystal structures modified dopamine mutations mimicking hGAT-1 indicated alternative tiagabine analogues that were found to block outward-open state, which is more consistent results previous...
Abstract Discovering hit compounds and optimization processes in medicinal chemistry nowadays could be improved by predictive tools, based on the relationship between structure of molecules lipophilic properties. Lipophilicity drug candidate can affect both pharmacokinetic pharmacodynamics properties, particular, ability a molecule to cross cell membrane. Among new methods for determination lipophilicity compounds, micellar electrokinetic chromatography (MEKC) is considered an appropriate...