This study addresses a comprehensive assessment of the interaction between chemical warfare agents (CWA) and acetylcholinesterase (AChE) systems, focus on the intriguing pnictogen-bond interaction (PnB). Utilizing the crystallographic data from the Protein Data Bank pertaining to the AChE-CWA complex involving Sarin (GB), Cyclosarin (GF), 2-[fluoro(methyl)phosphoryl]oxy-1,1-dimethylcyclopentane (GP) and venomous agent X (VX) agents, the CWA is systematically displaced by increments of 0.1 Å along the PO bond axis, extending its distance by 4 Å from the original position. The AIM analysis was carried out and consistently revealed the presence of a significant interaction along the PO bond. Investigating the intrinsic nature of the PnB, the NBO and the EDA analysis unearthed the contribution of orbital factors to the overall energy of the system. Strikingly, this observation challenges the conventional σ-hole explanation commonly associated with such interactions. This finding adds a layer of complexity to understanding of PnB, encouraging further exploration into the underlying mechanisms governing these intriguing chemical phenomena.

• Klíčová slova
• AIM analysis, NBO analysis, PO bonding, chemical warfare agents, pnictogen‐bond interaction,
• MeSH
• acetylcholinesterasa * chemie   metabolismus   MeSH
• chemické bojové látky * chemie   MeSH
• cholinesterasové inhibitory chemie   MeSH
• organofosforové sloučeniny chemie   MeSH
• sarin chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa * MeSH
• chemické bojové látky * MeSH
• cholinesterasové inhibitory MeSH
• organofosforové sloučeniny MeSH
• sarin MeSH

Chronic treatment with acetylcholinesterase inhibitors may be a promising therapeutic strategy for treatment of cardiovascular diseases. The aim of our study was to analyze the changes in blood pressure (BP) and heart rate (HR) during 14 days of treatment with two different acetylcholinesterase inhibitors - pyridostigmine (PYR) having only peripheral effects or donepezil (DON) with both peripheral and central effects. In addition, we studied their effects on the cardiovascular response to restraint stress and on sympathovagal control of HR in normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). SHR were characterized by elevated BP and increased low-frequency component of systolic BP variability (LF-SBPV), but their cardiac vagal tone and HR variability (HRV) were reduced compared with WKY. Chronic treatment with either acetylcholinesterase inhibitor decreased HR and increased HRV in both strains. PYR treatment slightly decreased BP and LF-SBPV in the dark phase of the day. Neither drug significantly altered BP response to stress, but PYR attenuated HR increase during restraint stress. Regarding sympathovagal balance, acute methylatropine administration caused a greater increase of HR in WKY than in SHR. Chronic PYR or DON treatment enhanced HRV and HR response to methylatropine (vagal tone) in WKY, whereas PYR but not DON treatment potentiated HRV and vagal tone in SHR. In conclusion, vagal tone was lower in SHR compared with WKY, but was enhanced by chronic PYR treatment in both strains. Thus, chronic peripheral, but not central, acetylcholinesterase inhibition has major effects on HR and its variability in both normotensive and hypertensive rats.

• Klíčová slova
• Acetylcholinesterase inhibitors, Parasympathetic tone, Spontaneously hypertensive rats, Sympathetic tone, Sympathovagal control of heart rate, Wistar-Kyoto rats,
• MeSH
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory farmakologie   terapeutické užití   MeSH
• deriváty atropinu * MeSH
• donepezil farmakologie   MeSH
• hypertenze * farmakoterapie   MeSH
• krevní tlak MeSH
• krysa rodu Rattus MeSH
• potkani inbrední SHR MeSH
• potkani inbrední WKY MeSH
• pyridostigmin-bromid * farmakologie   MeSH
• srdeční frekvence MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• deriváty atropinu * MeSH
• donepezil MeSH
• methylatropine MeSH Prohlížeč
• pyridostigmin-bromid * MeSH

The current study imposes a new class of organophosphorus (OP)-inhibited cholinesterase reactivators by conceptualizing a family of asymmetric bisoximes with various reactivating scaffolds. Several novel nucleophilic warheads were investigated, putting forward 29 novel reactivating options, by evaluating their nucleophilicity and ability to directly decompose OP compounds. Adopting the so-called zwitterionic strategy, 17 mono-oxime and nine bisoxime reactivators were discovered with major emphasis on the bifunctional-moiety approach. Compounds were compared with clinically used standards and other known experimentally highlighted reactivators. Our results clearly favor the concept of asymmetric bisoximes as leading reactivators in terms of efficacy and versatility. These top-ranked compounds were characterized in detail by reactivation kinetics parameters and evaluated for potential CNS availability. The highlighted molecules 55, 57, and 58 with various reactivating warheads, surpassed the reactivating potency of pralidoxime and several notable uncharged reactivators. The versatility of lead drug candidate 55 was also inspected on OP-inhibited butyrylcholinesterase, revealing a much higher rate compared to existing clinical antidotes.

• Klíčová slova
• Acetylcholinesterase, Butyrylcholinesterase, Nerve agents, Oxime, Pesticides, Reactivator,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• antidota chemie   farmakologie   MeSH
• butyrylcholinesterasa * metabolismus   chemie   MeSH
• cholinesterasové inhibitory chemie   farmakologie   MeSH
• kinetika MeSH
• lidé MeSH
• organofosforové sloučeniny chemie   MeSH
• otrava organofosfáty * farmakoterapie   MeSH
• oximy * chemie   farmakologie   MeSH
• reaktivátory cholinesterázy * chemie   farmakologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• antidota MeSH
• butyrylcholinesterasa * MeSH
• cholinesterasové inhibitory MeSH
• organofosforové sloučeniny MeSH
• oximy * MeSH
• reaktivátory cholinesterázy * MeSH

Selective activation of individual subtypes of muscarinic receptors is a promising way to safely alleviate a wide range of pathological conditions in the central nervous system and the periphery as well. The flexible G-protein interface of muscarinic receptors allows them to interact with several G-proteins with various efficacy, potency, and kinetics. Agonists biased to the particular G-protein mediated pathway may result in selectivity among muscarinic subtypes and, due to the non-uniform expression of individual G-protein alpha subunits, possibly achieve tissue specificity. Here, we demonstrate that novel tetrahydropyridine-based agonists exert specific signalling profiles in coupling with individual G-protein α subunits. These signalling profiles profoundly differ from the reference agonist carbachol. Moreover, coupling with individual Gα induced by these novel agonists varies among subtypes of muscarinic receptors which may lead to subtype selectivity. Thus, the novel tetrahydropyridine-based agonist can contribute to the elucidation of the mechanism of pathway-specific activation of muscarinic receptors and serve as a starting point for the development of desired selective muscarinic agonists.

• MeSH
• agonisté muskarinových receptorů * farmakologie   MeSH
• CHO buňky MeSH
• Cricetulus MeSH
• karbachol farmakologie   MeSH
• lidé MeSH
• proteiny vázající GTP - alfa-podjednotky metabolismus   genetika   MeSH
• proteiny vázající GTP metabolismus   MeSH
• pyridiny farmakologie   MeSH
• receptory muskarinové * metabolismus   MeSH
• signální transdukce účinky léků   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• agonisté muskarinových receptorů * MeSH
• karbachol MeSH
• proteiny vázající GTP - alfa-podjednotky MeSH
• proteiny vázající GTP MeSH
• pyridiny MeSH
• receptory muskarinové * MeSH

A-series agent A-234 belongs to a new generation of nerve agents. The poisoning of a former Russian spy Sergei Skripal and his daughter in Salisbury, England, in March 2018 led to the inclusion of A-234 and other A-series agents into the Chemical Weapons Convention. Even though five years have already passed, there is still very little information on its chemical properties, biological activities, and treatment options with established antidotes. In this article, we first assessed A-234 stability in neutral pH for subsequent experiments. Then, we determined its inhibitory potential towards human recombinant acetylcholinesterase (HssAChE; EC 3.1.1.7) and butyrylcholinesterase (HssBChE; EC 3.1.1.8), the ability of HI-6, obidoxime, pralidoxime, methoxime, and trimedoxime to reactivate inhibited cholinesterases (ChEs), its toxicity in rats and therapeutic effects of different antidotal approaches. Finally, we utilized molecular dynamics to explain our findings. The results of spontaneous A-234 hydrolysis showed a slow process with a reaction rate displaying a triphasic course during the first 72 h (the residual concentration 86.2%). A-234 was found to be a potent inhibitor of both human ChEs (HssAChE IC50 = 0.101 ± 0.003 µM and HssBChE IC50 = 0.036 ± 0.002 µM), whereas the five marketed oximes have negligible reactivation ability toward A-234-inhibited HssAChE and HssBChE. The acute toxicity of A-234 is comparable to that of VX and in the context of therapy, atropine and diazepam effectively mitigate A-234 lethality. Even though oxime administration may induce minor improvements, selected oximes (HI-6 and methoxime) do not reactivate ChEs in vivo. Molecular dynamics implies that all marketed oximes are weak nucleophiles, which may explain the failure to reactivate the A-234 phosphorus-serine oxygen bond characterized by low partial charge, in particular, HI-6 and trimedoxime oxime oxygen may not be able to effectively approach the A-234 phosphorus, while pralidoxime displayed low interaction energy. This study is the first to provide essential experimental preclinical data on the A-234 compound.

• Klíčová slova
• Acute toxicity, Hydrolysis, Nerve agent A-234, Reactivation, Therapy,
• MeSH
• acetylcholinesterasa MeSH
• antidota farmakologie   MeSH
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory toxicita   MeSH
• fosfor MeSH
• krysa rodu Rattus MeSH
• kyslík MeSH
• lidé MeSH
• oximy farmakologie   MeSH
• pralidoximové sloučeniny * MeSH
• pyridinové sloučeniny farmakologie   MeSH
• reaktivátory cholinesterázy * farmakologie   MeSH
• taurin analogy a deriváty   MeSH
• trimedoxim farmakologie   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu Rattus MeSH
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 2-(N-cyclohexylamino)ethanesulfonic acid MeSH Prohlížeč
• acetylcholinesterasa MeSH
• antidota MeSH
• asoxime chloride MeSH Prohlížeč
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• fosfor MeSH
• kyslík MeSH
• N,N'-monomethylenebis(pyridiniumaldoxime) MeSH Prohlížeč
• oximy MeSH
• pralidoxime MeSH Prohlížeč
• pralidoximové sloučeniny * MeSH
• pyridinové sloučeniny MeSH
• reaktivátory cholinesterázy * MeSH
• taurin MeSH
• trimedoxim MeSH

The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on the discovery of disease-modifying agents. Given the complexity of the disease, such an aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact the disease pathophysiology more comprehensively. Herewith, we contemplated the therapeutic efficacy of an amiridine drug acting as a cholinesterase inhibitor by converting it into a novel class of novel MTDLs. Applying the linking approach, we have paired amiridine as a core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties to generate novel MTDLs endowed with additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, and anti-amyloid properties, respectively. The top-ranked amiridine-based compound 5d was also inspected by in silico to reveal the butyrylcholinesterase binding differences with its close structural analogue 5b. Our study provides insight into the discovery of novel amiridine-based drugs by broadening their target-engaged profile from cholinesterase inhibitors towards MTDLs with potential implications in AD therapy.

• Klíčová slova
• Acetylcholinesterase, Amiridine, Antioxidant capacity, Butyrylcholinesterase, Multi-target directed ligands, NMDA receptors,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc * farmakoterapie   metabolismus   MeSH
• aminochinoliny terapeutické užití   MeSH
• butyrylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory * farmakologie   terapeutické užití   chemie   MeSH
• lidé MeSH
• ligandy MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• aminochinoliny MeSH
• amiridine MeSH Prohlížeč
• butyrylcholinesterasa MeSH
• cholinesterasové inhibitory * MeSH
• ligandy MeSH

BACKGROUND: Functional connectivity changes in clinically overt neurodegenerative diseases such as dementia with Lewy bodies have been described, but studies on connectivity changes in the pre-dementia phase are scarce. OBJECTIVES: We concentrated on evaluating striato-cortical functional connectivity differences between patients with Mild Cognitive Impairment with Lewy bodies and healthy controls and on assessing the relation to cognition. METHODS: Altogether, we enrolled 77 participants (47 patients, of which 35 met all the inclusion criteria for the final analysis, and 30 age- and gender-matched healthy controls, of which 28 met all the inclusion criteria for the final analysis) to study the seed-based connectivity of the dorsal, middle, and ventral striatum. We assessed correlations between functional connectivity in the regions of between-group differences and neuropsychological scores of interest (visuospatial and executive domains z-scores). RESULTS: Subjects with Mild Cognitive Impairment with Lewy Bodies, as compared to healthy controls, showed increased connectivity from the dorsal part of the striatum particularly to the bilateral anterior part of the temporal cortex with an association with executive functions. CONCLUSIONS: We were able to capture early abnormal connectivity within cholinergic and noradrenergic pathways that correlated with cognitive functions known to be linked to cholinergic/noradrenergic deficits. The knowledge of specific alterations may improve our understanding of early neural changes in pre-dementia stages and enhance research of disease modifying therapy.

• MeSH
• Alzheimerova nemoc * metabolismus   MeSH
• cholinergní látky metabolismus   MeSH
• demence s Lewyho tělísky * komplikace   MeSH
• exekutivní funkce MeSH
• kognice MeSH
• kognitivní dysfunkce * etiologie   komplikace   MeSH
• lidé MeSH
• mozek metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinergní látky MeSH

Environmental screening is essential due to the increased occurrence of harmful substances in the environment. Open Meter Duo (OMD) is an open-source field photo/fluorimeter that uses an RGB diode that imitates a color according to the selected wavelength and uses a UV LED from the security kit diode as an excitation light source. The prepared PCB shield with a 3D-printed aperture was connected to Arduino UNO R4 WiFi. This system was used for the fluorescent detection of cholinesterase activity with the indoxyl acetate method. Carbofuran-a toxic pesticide-and donepezil-a drug used to treat Alzheimer's disease-were tested as model inhibitors of cholinesterase activity. The limit of detection of indoxyl acetate was 11.6 μmol/L, and the IC50 values of the inhibitors were evaluated. This system is optimized for wireless use in field analysis with added cloud support and power source. The time of analysis was 5 min for the fluorimetric assay and 20 min for the optional photometric assay. The time of field operation was approximately 4 h of continuous measurement. This system is ready to be used as a cheap and easy control platform for portable use in drug control and point-of-care testing.

• Klíčová slova
• 3D printing, Arduino, cholinesterase, fluorimetry, low cost, portable, remote sensing,
• MeSH
• Alzheimerova nemoc * MeSH
• cholinesterasové inhibitory terapeutické užití   MeSH
• cholinesterasy terapeutické užití   MeSH
• donepezil terapeutické užití   MeSH
• fluorometrie MeSH
• lidé MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH
• donepezil MeSH

Tacrine (THA), a long withdrawn drug, is still a popular scaffold used in medicinal chemistry, mainly for its good reactivity and multi-targeted effect. However, THA-associated hepatotoxicity is still an issue and must be considered in drug discovery based on the THA scaffold. Following our previously identified hit compound 7-phenoxytacrine (7-PhO-THA), we systematically explored the chemical space with 30 novel derivatives, with a focus on low hepatotoxicity, anticholinesterase action, and antagonism at the GluN1/GluN2B subtype of the NMDA receptor. Applying the down-selection process based on in vitro and in vivo pharmacokinetic data, two candidates, I-52 and II-52, selective GluN1/GluN2B inhibitors thanks to the interaction with the ifenprodil-binding site, have entered in vivo pharmacodynamic studies. Finally, compound I-52, showing only minor affinity to AChE, was identified as a lead candidate with favorable behavioral and neuroprotective effects using open-field and prepulse inhibition tests, along with scopolamine-based behavioral and NMDA-induced hippocampal lesion models. Our data show that compound I-52 exhibits low toxicity often associated with NMDA receptor ligands, and low hepatotoxicity, often related to THA-based compounds.

• Klíčová slova
• Acetylcholinesterase, Alzheimer's disease, Electrophysiology, Glutamate receptor, In vivo, Neuroprotection, Tacrine,
• MeSH
• acetylcholinesterasa metabolismus   MeSH
• Alzheimerova nemoc * farmakoterapie   MeSH
• cholinesterasové inhibitory chemie   MeSH
• cholinesterasy MeSH
• lékové postižení jater * MeSH
• lidé MeSH
• neuroprotektivní látky * farmakologie   terapeutické užití   MeSH
• piperidiny * MeSH
• receptory N-methyl-D-aspartátu MeSH
• takrin chemie   MeSH
• vazebná místa MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• acetylcholinesterasa MeSH
• cholinesterasové inhibitory MeSH
• cholinesterasy MeSH
• ifenprodil MeSH Prohlížeč
• neuroprotektivní látky * MeSH
• piperidiny * MeSH
• receptory N-methyl-D-aspartátu MeSH
• takrin MeSH

BACKGROUND: Subjective cognitive decline (SCD) is a risk factor for future cognitive impairment and dementia. It is uncertain whether the neurodegeneration of the cholinergic system is already present in SCD individuals. We aimed to review the current evidence about the association between SCD and biomarkers of degeneration in the cholinergic system. METHOD: Original articles were extracted from three databases: Pubmed, Web of Sciences, and Scopus, in January 2023. Two researchers screened the studies independently. RESULTS: A total of 11 research articles were selected. SCD was mostly based on amnestic cognitive complaints. Cholinergic system biomarkers included neuroimaging markers of basal forebrain volume, functional connectivity, transcranial magnetic stimulation, or biofluid. The evidence showed associations between basal forebrain atrophy, poorer connectivity of the cholinergic system, and SCD CONCLUSIONS: Degenerative changes in the cholinergic system can be present in SCD. Subjective complaints may help when identifying individuals with brain changes that are associated with cognitive impairment. These findings may have important implications in targeting individuals that may benefit from cholinergic-target treatments at very early stages of neurodegenerative diseases.

• Klíčová slova
• Basal forebrain, Basal nucleus of Meynert, Ch(4), Cholinergic system, Subjective cognitive impairment, Subjective memory complaints,
• MeSH
• Alzheimerova nemoc * MeSH
• biologické markery MeSH
• cholinergní látky MeSH
• kognitivní dysfunkce * diagnostické zobrazování   MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• neurozobrazování metody   MeSH
• pars basalis telencephali * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• biologické markery MeSH
• cholinergní látky MeSH