7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.

• MeSH
• acetylcholinesterasa metabolismus   MeSH
• cholinesterasové inhibitory chemická syntéza   chemie   farmakologie   MeSH
• lidé MeSH
• molekulární modely MeSH
• molekulární struktura MeSH
• obidoxim chlorid chemie   farmakologie   MeSH
• organothiofosforové sloučeniny chemie   farmakologie   MeSH
• oximy chemie   farmakologie   MeSH
• pralidoximové sloučeniny chemie   farmakologie   MeSH
• pyridiny chemie   farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Nerve agents and oxon forms of organophosphorus pesticides act as strong irreversible inhibitors of two cholinesterases in the human body: acetylcholinesterase (AChE; EC 3.1.1.7) and butyrylcholinesterase (BChE; EC 3.1.1.8), and are therefore highly toxic compounds. For the recovery of inhibited AChE, antidotes from the group of pyridinium or bispyridinium aldoxime reactivators (pralidoxime, obidoxime, HI-6) are used in combination with anticholinergics and anticonvulsives. Therapeutic efficacy of reactivators (called “oximes”) depends on their chemical structure and also the type of organophosphorus inhibitor. Three novel oximes (K131, K142, K153) with an oxime group in position four of the pyridinium ring were designed and then tested for their potency to reactivate human (Homo sapiens sapiens) AChE (HssACHE) and BChE (HssBChE) inhibited by the pesticide paraoxon (diethyl 4-nitrophenyl phosphate). According to the obtained results, none of the prepared oximes were able to satisfactorily reactivate paraoxon-inhibited cholinesterases. On the contrary, extraordinary activity of obidoxime in the case of paraoxon-inhibited HssAChE reactivation was confirmed. Additional docking studies pointed to possible explanations for these results.

• MeSH
• acetylcholinesterasa chemie   MeSH
• antidota chemická syntéza   farmakologie   MeSH
• butyrylcholinesterasa chemie   MeSH
• cholinesterasové inhibitory chemie   MeSH
• enzymatické testy MeSH
• erytrocyty účinky léků   enzymologie   MeSH
• insekticidy antagonisté a inhibitory   chemie   toxicita   MeSH
• interakční proteinové domény a motivy MeSH
• lidé MeSH
• obidoxim chlorid chemie   farmakologie   MeSH
• oximy chemická syntéza   farmakologie   MeSH
• paraoxon antagonisté a inhibitory   chemie   toxicita   MeSH
• reaktivátory cholinesterázy chemická syntéza   farmakologie   MeSH
• sekundární struktura proteinů MeSH
• simulace molekulového dockingu MeSH
• termodynamika MeSH
• vazba proteinů MeSH
• vztahy mezi strukturou a aktivitou MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Organophosphorus compounds (organophosphates and organophosphonates) exert their toxicity by phosphylating (i.e. either phosphorylating or phosphonylating) the serine hydroxyl group of the enzyme acetylcholinesterase (AChE) in its active center, thereby inhibiting this enzyme, which inactivates the neurotransmitter acetylcholine (ACh). This results in an accumulation of ACh and an “endogenous ACh poisoning”. Oximes, which can reactivate the inhibited enzyme by dephosphylation, are used in the therapy of organophosphorus compound poisoning. During the reactivation process, oximes become themselves phosphylated. Many of these phosphylated oximes are extremely potent AChE inhibitors, which may reduce their therapeutic efficacy. K-27 is a very promising experimental oxime. In the present study, logP values of phosphylated K-27 are estimated after “in-silico exposure” to a number of organophosphorus esters [ethyl-paraoxon, methylparaoxon, diisopropyl-fluoro-phosphate, VX, soman, tabun, sarin, cyclosarin]. These logP values are compared with those of the native oxime and possible therapeutic relevance is discussed. While our previously published data regarding obidoxime and pralidoxime show that phosphylation increases their lipophilicity, facilitating penetration into the brain where they can inhibit or re-inhibit enzymes, this conclusion does not hold with respect to K-27; phosphylation of K-27 does not generally increase lipophilicity. Possible consequences with regard to blood-brain-barrier passage, toxicity and therapeutic efficacy are discussed.

• MeSH
• antidota chemie   MeSH
• hematoencefalická bariéra účinky léků   MeSH
• hydrofobní a hydrofilní interakce * MeSH
• lidé MeSH
• obidoxim chlorid chemie   MeSH
• organofosfáty toxicita   MeSH
• organofosfonáty toxicita   MeSH
• organofosforové sloučeniny toxicita   MeSH
• otrava organofosfáty * farmakoterapie   MeSH
• oximy * chemie   MeSH
• pralidoximové sloučeniny chemie   MeSH
• reaktivátory cholinesterázy * chemie   MeSH
• Check Tag
• lidé MeSH

The ability of the newly developed bispyridinium compound K203 and its fluorinated analogue KR-22836 to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the currently available reactivator of acetylcholinesterase-obidoxime. Tabun-induced neurotoxicity and the neuroprotective effects of all tested oximes in combination with atropine in rats poisoned with tabun at a sublethal dose (200 μg/kg intramuscularly (i.m.); 80% of LD(50) value) were monitored by a functional observational battery at 24 hr after tabun challenge. The results indicate that all tested oximes combined with atropine were able to survive tabun-poisoned rats 24 hr after tabun challenge while one non-treated tabun-poisoned rat died within 24 hr after tabun poisoning. All tested oximes combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisoning but they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. While the ability to reduce tabun-induced acute neurotoxicity of obidoxime and K203 was similar, the neuroprotective efficacy of KR-22836 was slightly higher compared to other tested oximes. Thus, the newly developed fluorinated analogue of K203, called KR-22836, is able to slightly increase the neuroprotective effectiveness of antidotal treatment of acute tabun poisonings compared to K203 and currently available obidoxime.

• MeSH
• akutní nemoc MeSH
• autonomní nervový systém účinky léků   MeSH
• chemické bojové látky otrava   MeSH
• chování zvířat účinky léků   MeSH
• hyperkineze chemicky indukované   prevence a kontrola   MeSH
• krysa rodu rattus MeSH
• molekulární struktura MeSH
• neuroprotektivní látky aplikace a dávkování   chemie   terapeutické užití   MeSH
• neurotoxické syndromy etiologie   prevence a kontrola   MeSH
• obidoxim chlorid aplikace a dávkování   chemie   terapeutické užití   MeSH
• organofosfáty MeSH
• otrava organofosfáty MeSH
• oximy aplikace a dávkování   chemie   terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   chemie   terapeutické užití   MeSH
• svalový tonus účinky léků   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH

Obidoxime, a well-known bis-pyridinium reactivator, is often the preferred antidote of organophosphorus poisoning caused by pesticides and tabun. It is also considered to be an allosteric modulator of muscarinic receptors, preferably M2 sub-type. This study compared the effect of obidoxime and atropine in vivo and in vitro on the cholinergic stimulation of the rat heart (M2) and the urinary bladder (M3). The results showed that obidoxime exerts anti-muscarinic effects, that may play an important role in the treatment of organophosphourus poisoning, and that the muscarinic receptor inhibition profile shows M2 receptor selectivity. This anti-muscarinic effect is much smaller that the effect of atropine and might be due to the allosteric inhibition of the receptors. The results also indicate that the acetylcholinesterase inhibition and the muscarinic receptor antagonism occur at different concentrations and dose levels.

• MeSH
• antagonisté muskarinových receptorů farmakologie   MeSH
• atropin farmakologie   MeSH
• cholinesterasové inhibitory farmakologie   MeSH
• krysa rodu rattus MeSH
• močový měchýř účinky léků   MeSH
• molekulární struktura MeSH
• obidoxim chlorid chemie   farmakologie   MeSH
• organofosforové sloučeniny MeSH
• otrava organofosfáty MeSH
• reaktivátory cholinesterázy chemie   farmakologie   MeSH
• srdeční frekvence účinky léků   MeSH
• srdeční síně účinky léků   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Oxime reactivators HI-6, obidoxime, trimedoxime, K347 and K628 were investigated as drugs designed for treatment of tabun intoxication. The experiments were performed on rats in order to simulate real conditions. Rats were intoxicated with one LD(50 )of tabun and treated with atropine and mentioned reactivators. Activities of erythrocyte acetylcholinesterase (AChE), plasma butyrylcholinesterase (BChE) and brain AChE were measured as markers of reactivation efficacy. An estimation of low molecular weight antioxidant levels using cyclic voltammetry was the second examination parameter. The evaluation of cholinesterases activity showed good reactivation potency of blood AChE and plasma BChE by commercially available obidoxime and newly synthesized K347. The potency of oximes to reactivate brain AChE was lower due to the poor blood-brain barrier penetration of used compounds. Commercially available reactivator HI-6 and newly synthesized K628 caused oxidative stress measured by cyclic voltammetry as antioxidant level. The oxidative stress provoked by HI-6 and K628 was found to be significant on probability level P = 0.05. The others reactivators did not affect antioxidant levels. Copyright 2009 John Wiley & Sons, Ltd.

• MeSH
• acetylcholinesterasa krev   metabolismus   MeSH
• antidota aplikace a dávkování   chemie   terapeutické užití   MeSH
• atropin aplikace a dávkování   chemie   terapeutické užití   MeSH
• cholinesterasové inhibitory aplikace a dávkování   chemie   toxicita   MeSH
• injekce intramuskulární MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• LD50 MeSH
• molekulární konformace MeSH
• molekulová hmotnost MeSH
• mozek metabolismus   MeSH
• obidoxim chlorid aplikace a dávkování   chemie   terapeutické užití   MeSH
• organofosfáty aplikace a dávkování   chemie   toxicita   MeSH
• oxidační stres účinky léků   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   chemie   terapeutické užití   MeSH
• reaktivátory cholinesterázy farmakologie   chemie   MeSH
• testy akutní toxicity MeSH
• trimedoxim aplikace a dávkování   chemie   terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• práce podpořená grantem MeSH

INTRODUCTION: The ability of currently available reactivators to reactivate cyclosarin is low. The aim of this study was to determine the reactivating and therapeutic efficacy of newly developed oximes (K206, K269) compared with currently available oximes against cyclosarin. METHODS: Rats and mice received atropine or atropine + oxime intramuscularly (i.m.) before or after an i.m. dose of cyclosarin. Acetylcholine activity levels in blood and tissues were measured to calculate the reactivation efficacy and potency. RESULTS AND DISCUSSION: In vivo determined percentage of reactivation of cyclosarin-inhibited blood and tissue acetylcholinesterase (AChE) in poisoned rats showed that the potency of both newly developed oximes (K206, K269) to reactivate cyclosarin-inhibited AChE is comparable with that of obidoxime in blood and diaphragm, but slightly higher than that of obidoxime in brain. Their reactivating efficacy is significantly lower compared with that of the oxime HI-6. K206 and K269 are relatively effective in reducing cyclosarin-induced lethal toxic effects in mice. Their therapeutic efficacies exceed the therapeutic potency of obidoxime but not that of HI-6. CONCLUSIONS: K206 and K269 are as effective in the reactivation of cyclosarin-inhibited AChE in rats and in the reduction of lethal toxic effects of cyclosarin in mice as obidoxime, but because their reactivating and therapeutic potency is significantly lower than that of HI-6, they are not suitable replacements for the currently available oximes for the treatment of cyclosarin poisoning.

• MeSH
• atropin aplikace a dávkování   terapeutické užití   MeSH
• bránice enzymologie   MeSH
• chemické bojové látky otrava   MeSH
• cholinesterasové inhibitory otrava   MeSH
• cholinesterasy krev   metabolismus   MeSH
• financování organizované MeSH
• inbrední kmeny myší MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• LD50 MeSH
• molekulární struktura MeSH
• mozek enzymologie   MeSH
• myši MeSH
• obidoxim chlorid aplikace a dávkování   chemie   terapeutické užití   toxicita   MeSH
• organofosforové sloučeniny MeSH
• otrava organofosfáty MeSH
• otrava enzymologie   farmakoterapie   MeSH
• oximy aplikace a dávkování   chemie   terapeutické užití   toxicita   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   chemie   terapeutické užití   toxicita   MeSH
• reaktivátory cholinesterázy aplikace a dávkování   chemie   terapeutické užití   toxicita   MeSH
• výsledek terapie MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH

The aim of our study was to evaluate the impact of acetylcholinesterase reactivators--K027 [1-(4-carbamoyl pyridinium)-3-(4-hydroxyiminomethyl pyridinium) propane dibromide], HI-6 [1-(4-carbamoylpyridinium)-3-(2-hydroxyimino methylpyridinium) oxapropane dichloride] and obidoxime [1,3-bis(4-hydroxyiminomethyl pyridinium)oxapropane dichloride] on hepatic functions in vivo. Male Wistar rats were randomly divided to seven groups and intramuscularly administered with saline and acetylcholinesterase reactivators (K027, HI-6 and obidoxime) at doses of 5% LD(50) and 50% LD(50). Liver tissue samples were taken 24 hr after administration. Histochemical detection of lipid droplets and immunohistochemical detection of multidrug resistance protein 2 (Mrp2) were provided. Lipid droplet count in rat liver did not show any significant differences in animals administered with K027, HI-6 and obidoxime in comparison with the control group. Mrp2 protein expression significantly decreased when animals were administered with K027 at a dose of 50% LD(50) and HI-6 and obidoxime at doses of 5% LD(50) and 50% LD(50), when compared to the controls. No statistical differences of Mrp2 expression were measured when animals were administered with K027 at a dose of 5% LD(50) in comparison with control animals. We found impaired hepatic transporter function after administration of HI-6, obidoxime and higher concentration of K027, which might be the underlying mechanism of acetylcholinesterase reactivators' hepatotoxicity.

• MeSH
• ABC transportéry biosyntéza   MeSH
• financování organizované MeSH
• játra metabolismus   účinky léků   MeSH
• krysa rodu rattus MeSH
• LD50 MeSH
• metabolismus lipidů účinky léků   MeSH
• obidoxim chlorid chemie   toxicita   MeSH
• oximy chemie   toxicita   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny chemie   toxicita   MeSH
• reaktivátory cholinesterázy chemie   toxicita   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• ztučnělá játra chemicky indukované   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

The potency of newly developed monoxime bispyridinium compounds (K156, K203) in reactivating tabun-inhibited acetylcholinesterase and reducing tabun-induced lethal toxic effects was compared with commonly used oximes (obidoxime, trimedoxime, the oxime HI-6) using in vivo methods. Studies determining percentage of reactivation of tabun-inhibited blood and tissue acetylcholinesterase in poisoned rats showed that the reactivating efficacy of newly developed oxime K203 is comparable with obidoxime and trimedoxime in blood and higher than the reactivating potency of trimedoxime and obidoxime in diaphragm and brain, where the difference in reactivating efficacy of obidoxime, trimedoxime and K203 is significant. On the other hand, the potency of newly developed K156 to reactivate tabun-inhibited acetylcholinesterase is comparable with obidoxime or trimedoxime in diaphragm and brain. It is significantly lower than the reactivating efficacy of trimedoxime and obidoxime in blood. Moreover, both newly developed oximes were found to be relatively efficacious in the reduction of lethal toxic effects in tabun-poisoned mice. Especially, the oxime K203 is able to decrease the acute toxicity of tabun nearly two times. The therapeutic efficacy of K156 and K203 corresponds to their potency to reactivate tabun-inhibited acetylcholinesterase, especially in diaphragm and brain. In contrast to obidoxime and trimedoxime, the oxime HI-6 is not effective in reactivation of tabun-inhibited acetycholinesterase and in reducing tabun lethality. While the oxime K156 does not improve the reactivating and therapeutic effectiveness of currently available obidoxime and trimedoxime, the newly developed oxime K203 is markedly more effective in reactivation of tabun-inhibited acetylcholinesterase in rats, especially in brain, and in reducing lethal toxic effects of tabun in mice and, therefore, it is suitable for the replacement of commonly used oximes for the antidotal treatment of acute tabun poisoning.

• MeSH
• acetylcholinesterasa krev   metabolismus   MeSH
• antidota aplikace a dávkování   chemie   terapeutické užití   MeSH
• atropin aplikace a dávkování   chemie   terapeutické užití   MeSH
• cholinesterasové inhibitory aplikace a dávkování   chemie   otrava   MeSH
• druhová specificita MeSH
• financování organizované MeSH
• injekce intramuskulární MeSH
• kombinovaná farmakoterapie MeSH
• krysa rodu rattus MeSH
• LD50 MeSH
• molekulární struktura MeSH
• myši MeSH
• obidoxim chlorid aplikace a dávkování   chemie   terapeutické užití   MeSH
• organofosfáty aplikace a dávkování   chemie   MeSH
• otrava organofosfáty MeSH
• oximy aplikace a dávkování   chemie   terapeutické užití   MeSH
• potkani Wistar MeSH
• pyridinové sloučeniny aplikace a dávkování   chemie   terapeutické užití   MeSH
• reaktivátory cholinesterázy aplikace a dávkování   chemie   terapeutické užití   MeSH
• testy akutní toxicity metody   MeSH
• trimedoxim aplikace a dávkování   chemie   terapeutické užití   MeSH
• vysokoúčinná kapalinová chromatografie MeSH
• záchvaty enzymologie   chemicky indukované   prevence a kontrola   MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH

In vitro comparison of reactivation efficacy of five currently used oximes - pralidoxime, obidoxime, trimedoxime, methoxime, and HI-6 (at two concentrations: 10-5 and 10-3 M) - against acetylcholinesterase (AChE; E.C. 3.1.1.7) inhibited by six different nerve agents (VX, Russian VX, sarin, cyclosarin, tabun, soman) and organophosphorus insecticide chlorpyrifos was the aim of this study. As a source of AChE in the experiments, rat brain homogenate was used. According to the results obtained, no AChE reactivator was able to reach sufficient potency for AChE inhibited by all nerve agents used. Moreover, oxime HI-6 (the most effective one) was not able to reactivate tabun- and soman-inhibited AChE. Due to this fact, it could be designated as a partially broad-spectrum reactivator.

• MeSH
• chemické bojové látky chemie   toxicita   MeSH
• cholinesterasové inhibitory chemie   toxicita   MeSH
• dursban chemie   toxicita   MeSH
• financování organizované MeSH
• krysa rodu rattus MeSH
• mozek enzymologie   MeSH
• obidoxim chlorid farmakologie   chemie   MeSH
• organofosfáty chemie   toxicita   MeSH
• organofosforové sloučeniny chemie   toxicita   MeSH
• organothiofosforové sloučeniny chemie   toxicita   MeSH
• oximy farmakologie   chemie   MeSH
• potkani Wistar MeSH
• pralidoximové sloučeniny farmakologie   chemie   MeSH
• pyridinové sloučeniny farmakologie   chemie   MeSH
• reaktivátory cholinesterázy farmakologie   chemie   MeSH
• sarin chemie   toxicita   MeSH
• soman chemie   toxicita   MeSH
• tkáňové extrakty MeSH
• trimedoxim farmakologie   chemie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• krysa rodu rattus MeSH
• zvířata MeSH
• Publikační typ
• srovnávací studie MeSH