Konecny J


Full name : Konecny Jan

First name : Jan

Mail : Biomedical Research Centre, University Hospital Hradec Kralove, Sokolska 581, 500 05 Hradec Kralove

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Country : Czech Republic

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References (8)

Title : A-agents, misleadingly known as Novichoks: a narrative review - Opravil_2023_Arch.Toxicol__
Author(s) : Opravil J , Pejchal J , Finger V , Korabecny J , Rozsypal T , Hrabinova M , Muckova L , Hepnarova V , Konecny J , Soukup O , Jun D
Ref : Archives of Toxicology , : , 2023
Abstract : "Novichok" refers to a new group of nerve agents called the A-series agents. Their existence came to light in 2018 after incidents in the UK and again in 2020 in Russia. They are unique organophosphorus-based compounds developed during the Cold War in a program called Foliant in the USSR. This review is based on original chemical entities from Mirzayanov's memoirs published in 2008. Due to classified research, a considerable debate arose about their structures, and hence, various structural moieties were speculated. For this reason, the scientific literature is highly incomplete and, in some cases, contradictory. This review critically assesses the information published to date on this class of compounds. The scope of this work is to summarize all the available and relevant information, including the physicochemical properties, chemical synthesis, mechanism of action, toxicity, pharmacokinetics, and medical countermeasures used to date. The environmental stability of A-series agents, the lack of environmentally safe decontamination, their high toxicity, and the scarcity of information on post-contamination treatment pose a challenge for managing possible incidents.
ESTHER : Opravil_2023_Arch.Toxicol__
PubMedSearch : Opravil_2023_Arch.Toxicol__
PubMedID: 37612377

Title : UHPLC-Orbitrap study of the first phase tacrine in vitro metabolites and related Alzheimer's drug candidates using human liver microsomes - Novak_2023_J.Pharm.Biomed.Anal_224_115154
Author(s) : Novak M , Svobodova B , Konecny J , Kuratkova A , Nevosadova L , Prchal L , Korabecny J , Lauschke VM , Soukup O , Kucera R
Ref : J Pharm Biomed Anal , 224 :115154 , 2023
Abstract : Tacrine was the first drug used in the therapy of Alzheimer's disease (AD) and is one of the leading structures frequently pursued in the drug discovery of novel candidates for tackling AD. However, because tacrine has been withdrawn from the market due to its hepatotoxicity, ascribed to specific metabolites, concerns are high about the toxicity profile of newly developed compounds related to tacrine. From the point of view of drug safety, the formation of metabolites must be uncovered and analyzed. Bearing in mind that the main culprit of tacrine hepatotoxicity is its biotransformation to hydroxylated metabolites, human liver microsomes were used as a biotransformation model. Our study aims to clarify phase I metabolites of three potentially non-toxic tacrine derivatives (7-methoxytacrine, 6-chlorotacrine, 7-phenoxytacrine) and to semi-quantitatively determine the relative amount of individual metabolites as potential culprits of tacrine-based hepatotoxicity. For this purpose, a new selective UHPLC-Orbitrap method has been developed. Applying UHPLC-Orbitrap method, two as yet unpublished tacrine and 7-methoxytacrine monohydroxylated metabolites have been found and completely characterized, and the separation of ten dihydroxylated tacrine and 7-methoxytacrine metabolites was achieved for the first time. Moreover, the structures of several new metabolites of 7-phenoxytacrine and 6-chlorotacrine have been identified. In addition, the relative amount of these newly observed metabolites was determined. Based on the results and known facts about the toxicity of tacrine metabolites published so far, it appears that 7-phenoxytacrine and 6-chlorotacrine could be substantially less hepatotoxic compared to tacrine, and could potentially pave the way for metabolically safe molecules applicable in AD therapy.
ESTHER : Novak_2023_J.Pharm.Biomed.Anal_224_115154
PubMedSearch : Novak_2023_J.Pharm.Biomed.Anal_224_115154
PubMedID: 36442458

Title : Neurotoxicity evoked by organophosphates and available countermeasures - Pulkrabkova_2022_Arch.Toxicol__
Author(s) : Pulkrabkova L , Svobodova B , Konecny J , Kobrlova T , Muckova L , Janousek J , Pejchal J , Korabecny J , Soukup O
Ref : Archives of Toxicology , : , 2022
Abstract : Organophosphorus compounds (OP) are a constant problem, both in the military and in the civilian field, not only in the form of acute poisoning but also for their long-lasting consequences. No antidote has been found that satisfactorily protects against the toxic effects of organophosphates. Likewise, there is no universal cure to avert damage after poisoning. The key mechanism of organophosphate toxicity is the inhibition of acetylcholinesterase. The overstimulation of nicotinic or muscarinic receptors by accumulated acetylcholine on a synaptic cleft leads to activation of the glutamatergic system and the development of seizures. Further consequences include generation of reactive oxygen species (ROS), neuroinflammation, and the formation of various other neuropathologists. In this review, we present neuroprotection strategies which can slow down the secondary nerve cell damage and alleviate neurological and neuropsychiatric disturbance. In our opinion, there is no unequivocal approach to ensure neuroprotection, however, sooner the neurotoxicity pathway is targeted, the better the results which can be expected. It seems crucial to target the key propagation pathways, i.e., to block cholinergic and, foremostly, glutamatergic cascades. Currently, the privileged approach oriented to stimulating GABA(A)R by benzodiazepines is of limited efficacy, so that antagonizing the hyperactivity of the glutamatergic system could provide an even more efficacious approach for terminating OP-induced seizures and protecting the brain from permanent damage. Encouraging results have been reported for tezampanel, an antagonist of GluK1 kainate and AMPA receptors, especially in combination with caramiphen, an anticholinergic and anti-glutamatergic agent. On the other hand, targeting ROS by antioxidants cannot or already developed neuroinflammation does not seem to be very productive as other processes are also involved.
ESTHER : Pulkrabkova_2022_Arch.Toxicol__
PubMedSearch : Pulkrabkova_2022_Arch.Toxicol__
PubMedID: 36335468

Title : Pursuing the Complexity of Alzheimer's Disease: Discovery of Fluoren-9-Amines as Selective Butyrylcholinesterase Inhibitors and N-Methyl-d-Aspartate Receptor Antagonists - Konecny_2020_Biomolecules_11_
Author(s) : Konecny J , Misiachna A , Hrabinova M , Pulkrabkova L , Benkova M , Prchal L , Kucera T , Kobrlova T , Finger V , Kolcheva M , Kortus S , Jun D , Valko M , Horak M , Soukup O , Korabecny J
Ref : Biomolecules , 11 : , 2020
Abstract : Alzheimer's disease (AD) is a complex disorder with unknown etiology. Currently, only symptomatic therapy of AD is available, comprising cholinesterase inhibitors and N-methyl-d-aspartate (NMDA) receptor antagonists. Drugs targeting only one pathological condition have generated only limited efficacy. Thus, combining two or more therapeutic interventions into one molecule is believed to provide higher benefit for the treatment of AD. In the presented study, we designed, synthesized, and biologically evaluated 15 novel fluoren-9-amine derivatives. The in silico prediction suggested both the oral availability and permeation through the blood-brain barrier (BBB). An initial assessment of the biological profile included determination of the cholinesterase inhibition and NMDA receptor antagonism at the GluN1/GluN2A and GluN1/GluN2B subunits, along with a low cytotoxicity profile in the CHO-K1 cell line. Interestingly, compounds revealed a selective butyrylcholinesterase (BChE) inhibition pattern with antagonistic activity on the NMDARs. Their interaction with butyrylcholinesterase was elucidated by studying enzyme kinetics for compound 3c in tandem with the in silico docking simulation. The docking study showed the interaction of the tricyclic core of new derivatives with Trp82 within the anionic site of the enzyme in a similar way as the template drug tacrine. From the kinetic analysis, it is apparent that 3c is a competitive inhibitor of BChE.
ESTHER : Konecny_2020_Biomolecules_11_
PubMedSearch : Konecny_2020_Biomolecules_11_
PubMedID: 33375115

Title : From orexin receptor agonist YNT-185 to novel antagonists with drug-like properties for the treatment of insomnia - Mezeiova_2020_Bioorg.Chem_103_104179
Author(s) : Mezeiova E , Janockova J , Konecny J , Kobrlova T , Benkova M , Dolezal R , Prchal L , Karasova-Zdarova J , Soukup O , Korabecny J
Ref : Bioorg Chem , 103 :104179 , 2020
Abstract : YNT-185 is the first known small molecule acting as orexin 2 receptor (OX(2)R) agonist with implication to narcolepsy treatment, served as a template scaffold in generating a small set of seven compounds with predictive affinity to OX(2)R. The design of the new small molecules was driven mostly by improving physicochemical properties of the parent drug YNT-185 in parallel with in silico studies, later suggesting their favorable binding modes within the active site of OX(2)R. We obtained seven new potential OX(2)R binders that were evaluated in vitro for their CNS availability, cytotoxicity, and behavior pattern on OX(2)R. Out of them, 15 emerged as the most potent modulator of OX(2)R, which, contrary to YNT-185, displayed inverse mode of action, i.e. antagonist profile. 15 was also submitted to an in vivo experiment revealing its ability to permeate through BBB into the brain with a short half-life.
ESTHER : Mezeiova_2020_Bioorg.Chem_103_104179
PubMedSearch : Mezeiova_2020_Bioorg.Chem_103_104179
PubMedID: 32891860

Title : Orexin supplementation in narcolepsy treatment: A review - Nepovimova_2019_Med.Res.Rev_39_961
Author(s) : Nepovimova E , Janockova J , Misik J , Kubik S , Stuchlik A , Vales K , Korabecny J , Mezeiova E , Dolezal R , Soukup O , Kobrlova T , Pham NL , Nguyen TD , Konecny J , Kuca K
Ref : Med Res Rev , 39 :961 , 2019
Abstract : Narcolepsy is a rare, chronic neurological disease characterized by excessive daytime sleepiness, cataplexy, vivid hallucinations, and sleep paralysis. Narcolepsy occurs in approximately 1 of 3000 people, affecting mainly adolescents aged 15 to 30 years. Recently, people with narcolepsy were shown to exhibit extensive orexin/hypocretin neuronal loss. The orexin system regulates sleep/wake control via complex interactions with monoaminergic, cholinergic and GABA-ergic neuronal systems. Currently, no cure for narcolepsy exists, but some symptoms can be controlled with medication (eg, stimulants, antidepressants, etc). Orexin supplementation represents a more sophisticated way to treat narcolepsy because it addresses the underlying cause of the disease and not just the symptoms. Research on orexin supplementation in the treatment of sleep disorders has strongly increased over the past two decades. This review focuses on a brief description of narcolepsy, the mechanisms by which the orexin system regulates sleep/wake cycles, and finally, possible therapeutic options based on orexin supplementation in animal models and patients with narcolepsy.
ESTHER : Nepovimova_2019_Med.Res.Rev_39_961
PubMedSearch : Nepovimova_2019_Med.Res.Rev_39_961
PubMedID: 30426515

Title : Investigation of New Orexin 2 Receptor Modulators Using In Silico and In Vitro Methods - Janockova_2018_Molecules_23_
Author(s) : Janockova J , Dolezal R , Nepovimova E , Kobrlova T , Benkova M , Kuca K , Konecny J , Mezeiova E , Melikova M , Hepnarova V , Ring A , Soukup O , Korabecny J
Ref : Molecules , 23 : , 2018
Abstract : The neuropeptides, orexin A and orexin B (also known as hypocretins), are produced in hypothalamic neurons and belong to ligands for orphan G protein-coupled receptors. Generally, the primary role of orexins is to act as excitatory neurotransmitters and regulate the sleep process. Lack of orexins may lead to sleep disorder narcolepsy in mice, dogs, and humans. Narcolepsy is a neurological disorder of alertness characterized by a decrease of ability to manage sleep-wake cycles, excessive daytime sleepiness, and other symptoms, such as cataplexy, vivid hallucinations, and paralysis. Thus, the discovery of orexin receptors, modulators, and their causal implication in narcolepsy is the most important advance in sleep-research. The presented work is focused on the evaluation of compounds L1L11 selected by structure-based virtual screening for their ability to modulate orexin receptor type 2 (OX2R) in comparison with standard agonist orexin-A together with their blood-brain barrier permeability and cytotoxicity. We can conclude that the studied compounds possess an affinity towards the OX2R. However, the compounds do not have intrinsic activity and act as the antagonists of this receptor. It was shown that L4 was the most potent antagonistic ligand to orexin A and displayed an IC(50) of 2.2 microM, offering some promise mainly for the treatment of insomnia.
ESTHER : Janockova_2018_Molecules_23_
PubMedSearch : Janockova_2018_Molecules_23_
PubMedID: 30423961

Title : Continuous deacetylation of cephalosporins - Konecny_1980_Biotechnol.Bioeng_22_2013
Author(s) : Konecny J , Sieber M
Ref : Biotechnol Bioeng , 22 :2013 , 1980
Abstract : Continuous deacetylation of cephalosporin C, 7-aminocephalosporanic acid, and of 2-methoxyethyl acetate in packed beds of an immobilized esterase is described by simple empirical equations relating conversion to space velocity and temperature. The choice of process conditions is discussed in relation to the effects of temperature on column efficiency, column life, growth of microbial contaminants, and the rates of thermal decomposition of the substrates. At the preferred temperature of 10 degrees C columns were operated continuously for one month with only small losses in efficiency.
ESTHER : Konecny_1980_Biotechnol.Bioeng_22_2013
PubMedSearch : Konecny_1980_Biotechnol.Bioeng_22_2013
PubMedID: 29345758