- Klíčová slova
- pH detekční metody, histochemické metody,
- MeSH
- acetylcholinesterasa * farmakologie fyziologie nedostatek škodlivé účinky MeSH
- biosenzitivní techniky metody normy přístrojové vybavení MeSH
- butyrylcholinesterasa * farmakologie fyziologie nedostatek škodlivé účinky MeSH
- chemické techniky analytické * využití MeSH
- cholinesterasové inhibitory MeSH
- cholinesterasy farmakologie fyziologie MeSH
- imunohistochemie metody normy přístrojové vybavení MeSH
- kolorimetrie metody normy přístrojové vybavení trendy MeSH
- lidé MeSH
- radiometrie metody normy přístrojové vybavení využití MeSH
- spektrofotometrie metody normy přístrojové vybavení MeSH
- titrace metody normy přístrojové vybavení MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Exposure to the nerve agent soman is difficult to treat due to the rapid dealkylation of the soman-acetylcholinesterase (AChE) conjugate known as aging. Oxime antidotes commonly used to reactivate organophosphate inhibited AChE are ineffective against soman, while the efficacy of the recommended nerve agent bioscavenger butyrylcholinesterase is limited by strictly stoichiometric scavenging. To overcome this limitation, we tested ex vivo, in human blood, and in vivo, in soman exposed mice, the capacity of aging-resistant human AChE mutant Y337A/F338A in combination with oxime HI-6 to act as a catalytic bioscavenger of soman. HI-6 was previously shown in vitro to efficiently reactivate this mutant upon soman, as well as VX, cyclosarin, sarin, and paraoxon, inhibition. We here demonstrate that ex vivo, in whole human blood, 1 μM soman was detoxified within 30 min when supplemented with 0.5 μM Y337A/F338A AChE and 100 μM HI-6. This combination was further tested in vivo. Catalytic scavenging of soman in mice improved the therapeutic outcome and resulted in the delayed onset of toxicity symptoms. Furthermore, in a preliminary in vitro screen we identified an even more efficacious oxime than HI-6, in a series of 42 pyridinium aldoximes, and 5 imidazole 2-aldoxime N-propylpyridinium derivatives. One of the later imidazole aldoximes, RS-170B, was a 2-3-fold more effective reactivator of Y337A/F338A AChE than HI-6 due to the smaller imidazole ring, as indicated by computational molecular models, that affords a more productive angle of nucleophilic attack.
- MeSH
- acetylcholinesterasa genetika metabolismus farmakologie MeSH
- bodová mutace MeSH
- chemické bojové látky toxicita MeSH
- cholinesterasové inhibitory toxicita MeSH
- lidé MeSH
- molekulární modely MeSH
- myši MeSH
- oximy farmakologie MeSH
- pyridinové sloučeniny farmakologie MeSH
- reaktivátory cholinesterázy farmakologie MeSH
- soman toxicita MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
t is known that nerve agents are potent inhibitors of acetylcholinesterase (AChE), the enzyme responsible for the hydrolysis of the neurotransmitter acetylcholine and, thus, transmission of nerve impulses. The process of AChE inhibition by nerve agents can be reversed by a nucleophile able to dephosphorylate the enzyme. In this sense, oximes exhibit this characteristic and are able to remove the neurotoxic and reactivate AChE. Here, we review experimental and theoretical results involving docking and quantum mechanical-molecular mechanics hybrid methods (QM/MM), using Molegro® and Spartan® softwares to analyze the interaction of different nerve agents and oximes with AChE and to evaluate kinetic constants of reactivation.
- Klíčová slova
- QM/MM,
- MeSH
- acetylcholinesterasa * farmakologie účinky léků MeSH
- chemická válka MeSH
- krysa rodu rattus MeSH
- molekulární modely * MeSH
- myši MeSH
- neurotoxiny antagonisté a inhibitory škodlivé účinky MeSH
- organofosfáty * farmakologie škodlivé účinky MeSH
- oximy * farmakologie terapeutické užití MeSH
- simulace molekulového dockingu MeSH
- techniky in vitro MeSH
- vazba proteinů MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- hodnotící studie MeSH
- práce podpořená grantem MeSH
Background. Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology. Methods and Results. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer’s disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium). Conclusions. The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.
- MeSH
- acetylcholinesterasa farmakologie metabolismus MeSH
- Alzheimerova nemoc enzymologie farmakoterapie metabolismus MeSH
- butyrylcholinesterasa farmakologie metabolismus MeSH
- cholinesterasové inhibitory farmakologie terapeutické užití toxicita MeSH
- cholinesterasy farmakologie metabolismus MeSH
- molekulární struktura MeSH
- myasthenia gravis enzymologie farmakoterapie metabolismus MeSH
- organofosforové sloučeniny toxicita MeSH
- sarin farmakologie toxicita MeSH
- vazebná místa účinky léků MeSH
- vztahy mezi strukturou a aktivitou MeSH
Trimedoxime is a bisquaternary oxime that is widely used in the treatment of organophosphorous poisoning caused by tabun and paraoxon. We tested its affinity to acetylcholinesterase (AChE), its mechanism of interaction and effect on the cholinergic system of the rat bladder. The half maximal inhibitory concentration (IC50) of trimedoxime to recombinant AChE was found to be 82.0 mM ± 30.1 mM. This represents a weak inhibition. Its interaction with AChE seems to be very similar to obidoxime - one aromatic nucleus interacts with the peripheral anionic site and the other with the residues TYR337 and TYR341 inside the cavity. Also the oxime moiety is moving towards the catalytic triade ready for the reactivation of the inhibited AChE. In the organ bath experiment no significant effect of trimedoxime was observed on the contraction of the detrusor caused by the muscarinic agonist metacholine.
- Klíčová slova
- acetylcholinesterase, trimedoxime, antidote, muscaricnic receptors, reactivation,
- MeSH
- acetylcholinesterasa farmakokinetika farmakologie účinky léků MeSH
- antidota farmakologie terapeutické užití MeSH
- cholinergní antagonisté farmakokinetika farmakologie terapeutické užití MeSH
- cholinergní látky farmakologie imunologie izolace a purifikace MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- močový měchýř MeSH
- organofosforové sloučeniny farmakokinetika farmakologie toxicita MeSH
- pesticidy farmakokinetika farmakologie toxicita MeSH
- potkani Sprague-Dawley MeSH
- reaktivátory cholinesterázy farmakokinetika farmakologie terapeutické užití MeSH
- receptory muskarinové účinky léků MeSH
- synergismus léků MeSH
- trimedoxim farmakokinetika farmakologie metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- MeSH
- acetylcholinesterasa farmakologie účinky léků MeSH
- benaktyzin aplikace a dávkování chemie terapeutické užití MeSH
- cholinesterasové inhibitory škodlivé účinky toxicita MeSH
- experimenty na zvířatech statistika a číselné údaje MeSH
- financování organizované MeSH
- mozeček účinky léků MeSH
- mozek účinky léků MeSH
- organofosforové sloučeniny chemie škodlivé účinky toxicita MeSH
- oximy aplikace a dávkování chemie terapeutické užití MeSH
- potkani Wistar MeSH
- premedikace metody statistika a číselné údaje využití MeSH
- pyridostigmin-bromid aplikace a dávkování chemie terapeutické užití MeSH
- statistika jako téma MeSH
- takrin aplikace a dávkování chemie terapeutické užití MeSH
- trihexyfenidyl aplikace a dávkování chemie terapeutické užití MeSH
- zvířata MeSH
- Check Tag
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- tabulky MeSH
10-Methylacridinium iodide (methylacridinium; MA) is an inhibitor of cholinesterases. Inhibitors of acetylcholinesterase (AChE) are used in the treatment of myasthenia gravis, Alzheimer's disease, and in the prophylaxis of poisoning with organophosphates. Using spectrophotometric Ellman's method at 436 nm and commercial enzymes we found that MA inhibits AChE by binding with relatively high potency to the peripheral anionic site (IC(50) = 1.68 +/- 0.14 1M; human recombinant AChE) and equally to its inhibition of butyrylcholinesterase (BuChE; IC(50) = 3.54 +/- 0.27 1M; BuChE from human serum). MA also inhibits the binding of [(3)H]N-methylscopolamine to the muscarinic M2 receptor subtype, possibly in an allosteric manner (IC(50) = 1.90 1M). Functional effects on both the enzyme and the receptor could be observed in contractile studies on the isolated rat bladder. The ability of MA to cross the blood-brain barrier (log P = -0.32; polar surface area 3.88) provides prerequisites for a potential use of the drug in the treatment of neural disorders.
- MeSH
- acetylcholinesterasa farmakologie chemie MeSH
- akridiny chemie MeSH
- butyrylcholinesterasa farmakologie chemie krev MeSH
- chemické modely MeSH
- cholinergní látky farmakologie MeSH
- hematoencefalická bariéra fyziologie účinky léků MeSH
- inhibiční koncentrace 50 MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- močový měchýř metabolismus účinky léků MeSH
- myši MeSH
- počítačová simulace MeSH
- potkani Sprague-Dawley MeSH
- prasata MeSH
- regresní analýza MeSH
- sérum metabolismus MeSH
- srdce účinky léků MeSH
- substrátová specifita MeSH
- vazba proteinů účinky léků MeSH
- vazebná místa účinky léků MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
Organophosphorus pesticides such as parathion or chlorpyrifos are substances used worldwide for agricultural purposes. These compounds are able to inhibit an enzyme acetylcholinesterase (AChE; EC 3.1.1.7) by phosphorylation in its active site. AChE reactivators and anticholinergics are generally used as antidotes in the case of intoxication by these agents. In this work, the reactivation potency of nine structurally different AChE reactivators was tested in vitro. Chlorpyrifos was chosen as an appropriate member of the pesticide family. The result is that bisquaternary reactivators with two oxime groups in position four at the pyridinium rings (trimedoxime and K074) seem to be the most potent reactivators of chlorpyrifos-inhibited AChE.
- Klíčová slova
- Exelon, Aricept, Reninyl, Cerebrolysin,
- MeSH
- acetylcholinesterasa aplikace a dávkování farmakologie MeSH
- Alzheimerova nemoc farmakoterapie terapie MeSH
- biologická terapie metody trendy MeSH
- cholinesterasové inhibitory aplikace a dávkování farmakologie chemie MeSH
- demence farmakoterapie terapie MeSH
- lidé MeSH
- memantin aplikace a dávkování farmakologie MeSH
- N-methylaspartát aplikace a dávkování farmakologie chemie MeSH
- nervový růstový faktor analogy a deriváty aplikace a dávkování farmakologie MeSH
- nootropní látky aplikace a dávkování farmakologie MeSH
- scavengery volných radikálů aplikace a dávkování farmakologie MeSH
- Check Tag
- lidé MeSH
