A5052391526- Receptor Mechanisms and Signaling
- Neurotransmitter Receptor Influence on Behavior
- Neuroscience and Neuropharmacology Research
- Pharmacological Receptor Mechanisms and Effects
- Phenothiazines and Benzothiazines Synthesis and Activities
- Cholinesterase and Neurodegenerative Diseases
- Computational Drug Discovery Methods
- Phosphodiesterase function and regulation
- Synthesis and Biological Evaluation
- Drug Transport and Resistance Mechanisms
- Tryptophan and brain disorders
- Crystallization and Solubility Studies
- X-ray Diffraction in Crystallography
- Treatment of Major Depression
- Stress Responses and Cortisol
- Chemical synthesis and alkaloids
- Chemical Synthesis and Analysis
- Biochemical Analysis and Sensing Techniques
- Chemotherapy-induced cardiotoxicity and mitigation
- Bipolar Disorder and Treatment
- Adenosine and Purinergic Signaling
- Cancer therapeutics and mechanisms
- Neuropeptides and Animal Physiology
- Alzheimer's disease research and treatments
- Nicotinic Acetylcholine Receptors Study
Jagiellonian University
2015-2024
Medicina
2015-2024
Adamed (Poland)
2013-2024
Wroclaw Medical University
2003-2016
Institute of Medicinal Plant Development
2016
Lukasiewicz Research Network - Krakow Institute of Technology
2011
Polish Academy of Sciences
2004-2006
University of Iowa
2004
UCLouvain
1994-2002
Wrocław University of Science and Technology
1998
Pdr5p is the yeast <i>Saccharomyces cerevisiae</i> ATP-binding cassette transporter conferring resistance to several unrelated drugs. Its high overproduction in Pdr1p transcription factor mutants allows us study molecular mechanism of multidrug transport and substrate specificity. We have developed new <i>in vivo</i> vitro</i> assays Pdr5p-mediated drug transport. show that spite little sequence homology, inverted topology respect mammalian P-glycoproteins, shares with them common...
Multidrug resistance (MDR) mediated by broad specificity transporters is one of the most important strategies used pathogens, including cancer cells, to evade chemotherapy. In yeast Saccharomyces cerevisiae, a complex pleiotropic drug (PDR) network genes involved in MDR composed transcriptional regulators Pdr1p and Pdr3p, which activate expression ATP-binding cassette (ABC) transporters-encoding PDR5, SNQ2, YOR1 as well other not yet identified genes. We have screened 349 toxic compounds...
A 160-kDa plasma membrane protein of the yeast Saccharomyces cerevisiae was overexpressed by mutating PDR1 or PDR3 transcription factor gene. The is membrane-bound ATP binding cassette transporter PDR5 (Balzi, E., Wang, M., Leterme, S., Van Dyck, L., and Goffeau, A. (1994) J. Biol. Chem. 269, 2206-2214). solubilized with n-dodecyl-beta-D-malto-side separated from PMA1 H(+)-ATPase glycerol gradient centrifugation. hydrolyzes nucleoside diphosphates triphosphates. This activity sensitive to...
This paper describes a rhodopsin-based model of 5-HT1A serotonin receptor. The flexibility the receptor was considered by using large number models for ligand dockings. Rearrangements heptahelical bundle were introduced, which resulted in improvement correlation between computational results and experimental data. validated automated docking conformationally restricted arylpiperazines. Specific interactions, responsible recognition arylpiperazine derivatives, identified. An ionic bond formed...
In order to target behavioral and psychological symptoms of dementia (BPSD), we used molecular modeling-assisted design obtain novel multifunctional arylsulfonamide derivatives that potently antagonize 5-HT(6/7/2A) D2 receptors, without interacting with M1 receptors hERG channels. vitro studies confirmed their antagonism 5-HT(7/2A) weak interactions key antitargets (M1R hERG) associated side effects. Marked 5-HT6 receptor affinities were also observed, notably for...
Recent breakthroughs in crystallographic studies of G protein-coupled receptors (GPCRs), together with continuous progress molecular modeling methods, have opened new perspectives for structure-based drug discovery. A crucial enhancement this area was development induced fit docking procedures that allow optimization binding pocket conformation guided by the features its active ligands. In course our research program aimed at discovery novel antipsychotic agents, attention focused on...
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...
Although serotonin 5-HT1A receptors constitute attractive therapeutic targets, there is a lack of potential clinical candidates that have high degree selectivity and full agonist efficacy. Recently, novel receptor "biased agonists" F15599 (also known as NLX-101) F13714 been reported exhibit distinctive properties for in vitro signaling, neurochemical, electrophysiological effects, brain imaging. The present study characterized their effects rat models anxiety (elevated plus-maze, EPM, Vogel...
A set of 31 diversified 5-HT7 receptor antagonists was automatically docked to a conformational ensemble rhodopsin-based 5-HT7R models (flexible docking). It found that ergolines, aporphines, and tricyclic psychotropic agents were always in pocket formed by TMHs 4−6, besides the main ionic bond with Asp3.32, they had specific interactions Phe6.52, Phe6.51, Trp6.48, Ser5.42. The arylpiperidine, arylpiperazine, or β-carboline fragment complex ligands occupied same pocket, whereas terminal...
The anticonvulsant activity of several 1,2,4-triazole-3-thione derivatives on mouse maximal electroshock-induced seizures was tested in this study. Characteristic features all active compounds were rapid onset action and long lasting effect. Structure-activity observations showed that the probability obtaining exerting much higher when at least one phenyl rings attached to 1,2,4-triazole nucleus had a substituent para position. obtained results, moreover, permit us conclude despite...
5HT6 receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In present study we investigated idalopirdine (LuAE58054) a model obesity induced by high-fat diet. To induce rats, animals were treated feed fat content 40 %. Body was controlled amount water consumed...
We report the discovery of NLX-266 (31), an orally available and metabolically stable ERK1/2-biased 5-HT1A receptor agonist, which demonstrates both enhanced antidepressant antiparkinsonian-like activities. A new series 1-(1-benzoylpiperidin-4-yl)methanamine derivatives were synthesized screened for their affinity selectivity toward receptor. Notably, 31 exhibited exceptional binding (pKi > 10) (>1000×) over adrenergic α1 dopaminergic D2 receptors. In vitro functional assays revealed that...
In Saccharomyces cerevisiae , the transcription factors Pdr1p and Pdr3p activate expression of several genes, including PDR5 SNQ2 YOR1 which encode ATP‐binding cassette transporters that extrude dozens antifungals with overlapping but distinct specificity. this study, it was observed growth resistance to specific Pdr5p substrates rose upon disruption or coding region accompanied by increased efflux. Similarly, Yor1p‐ Snq2p‐specific deletion . The mRNA protein levels respective in parallel...
New potential treatments for disseminated fungal infections are needed, especially caused by the commonly drug-resistant pathogens Candida albicans and C. glabrata. These cause systemic candidiasis, a significant of mortality in immune-compromised patients. ABC transporters pleiotropic drug resistance subfamily, such as Cdr1p albicans, play an important role antifungal bioassay targets therapies against pathogens. We observed strong growth inhibitory activity methanol extract Dalea formosa...