Petrov KA

General

Full name : Petrov Konstantin A

First name : Konstantin A

Mail : Institute of Organic and Physical Chemistry\; Lab. of Chemical and Biological Researches\; 8\; Arbuzova Str.\; Kazan\; 420088

Zip Code :

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Country : Russia

Email : kpetrov2005@mail.ru

Phone : +78432727383

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References (45)

Title : Conjugates of nucleobases with triazole-hydroxamic acids for the reactivation of acetylcholinesterase and treatment of delayed neurodegeneration induced by organophosphate poisoning - Shulaeva_2023_Bioorg.Chem_141_106858
Author(s) : Shulaeva MM , Zueva IV , Nikolaev AE , Saifina LF , Sharafutdinova DR , Babaev VM , Semenov VE , Petrov KA
Ref : Bioorg Chem , 141 :106858 , 2023
Abstract : A series of new uncharged conjugates of adenine, 3,6-dimetyl-, 1,6-dimethyl- and 6-methyluracil with 1,2,4-triazole-3-hydroxamic and 1,2,3-triazole-4-hydroxamic acid moieties were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. It is shown that triazole-hydroxamic acids can reactivate acetylcholinesterase (AChE) inhibited by paraoxon (POX) in vitro, offering reactivation constants comparable to those of pralidoxime (2-PAM). However, in contrast to 2-PAM, triazole-hydroxamic acids demonstrated the ability to reactivate AChE in the brain of rats poisoned with POX. At a dose of 200 mg/kg (i.v.), the lead compound 3e reactivated 22.6 +/- 7.3% of brain AChE in rats poisoned with POX. In a rat model of POX-induced delayed neurodegeneration, compound 3e reduced the neuronal injury labeled with FJB upon double administration 1 and 3 h after poisoning. Compound 3e was also shown to prevent memory impairment of POX-poisoned rats as tested in a Morris water maze.
ESTHER : Shulaeva_2023_Bioorg.Chem_141_106858
PubMedSearch : Shulaeva_2023_Bioorg.Chem_141_106858
PubMedID: 37774432

Title : Can Activation of Acetylcholinesterase by beta-Amyloid Peptide Decrease the Effectiveness of Cholinesterase Inhibitors? - Zueva_2023_Int.J.Mol.Sci_24_
Author(s) : Zueva IV , Vasilieva EA , Gaynanova GA , Moiseenko AV , Burtseva AD , Boyko KM , Zakharova LY , Petrov KA
Ref : Int J Mol Sci , 24 : , 2023
Abstract : A central event in the pathogenesis of Alzheimer's disease (AD) is the accumulation of senile plaques composed of aggregated amyloid-beta (Abeta) peptides. The main class of drugs currently used for the treatment of AD are the acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitors. In this study, it has been shown that Abeta augmented AChE activity in vitro, maximum activation of 548 +/- 5% was achieved following 48 h of incubation with 10 microM of Abeta(1-40), leading to a 7.7-fold increase in catalytic efficiency. The observed non-competitive type of AChE activation by Abeta(1-40) was associated with increased V(max) and unchanged K(m). Although BChE activity also increased following incubation with Abeta(1-40), this was less efficiently achieved as compared with AChE. Ex vivo electrophysiological experiments showed that 10 microM of Abeta(1-40) significantly decreased the effect of the AChE inhibitor huperzine A on the synaptic potential parameters.
ESTHER : Zueva_2023_Int.J.Mol.Sci_24_
PubMedSearch : Zueva_2023_Int.J.Mol.Sci_24_
PubMedID: 38003588

Title : Oxime Therapy for Brain AChE Reactivation and Neuroprotection after Organophosphate Poisoning - Kuznetsova_2022_Pharmaceutics_14_
Author(s) : Kuznetsova DA , Gaynanova GA , Vasilieva EA , Pavlov RV , Zueva IV , Babaev VM , Kuznetsov DM , Voloshina AD , Petrov KA , Zakharova LY , Sinyashin OG
Ref : Pharmaceutics , 14 : , 2022
Abstract : One of the main problems in the treatment of poisoning with organophosphorus (OPs) inhibitors of acetylcholinesterase (AChE) is low ability of existing reactivators of AChE that are used as antidotes to cross the blood-brain barrier (BBB). In this work, modified cationic liposomes were developed that can penetrate through the BBB and deliver the reactivator of AChE pralidoxime chloride (2-PAM) into the brain. Liposomes were obtained on the basis of phosphatidylcholine and imidazolium surfactants. To obtain the composition optimized in terms of charge, stability, and toxicity, the molar ratio of surfactant/lipid was varied. For the systems, physicochemical parameters, release profiles of the substrates (rhodamine B, 2-PAM), hemolytic activity and ability to cause hemagglutination were evaluated. Screening of liposome penetration through the BBB, analysis of 2-PAM pharmacokinetics, and in vivo AChE reactivation showed that modified liposomes readily pass into the brain and reactivate brain AChE in rats poisoned with paraoxon (POX) by 25%. For the first time, an assessment was made of the ability of imidazolium liposomes loaded with 2-PAM to reduce the death of neurons in the brains of mice. It was shown that intravenous administration of liposomal 2-PAM can significantly reduce POX-induced neuronal death in the hippocampus.
ESTHER : Kuznetsova_2022_Pharmaceutics_14_
PubMedSearch : Kuznetsova_2022_Pharmaceutics_14_
PubMedID: 36145698

Title : Therapy of Organophosphate Poisoning via Intranasal Administration of 2-PAM-Loaded Chitosomes - Vasilieva_2022_Pharmaceutics_14_
Author(s) : Vasilieva EA , Kuznetsova DA , Valeeva FG , Kuznetsov DM , Zakharov AV , Amerhanova SK , Voloshina AD , Zueva IV , Petrov KA , Zakharova LY
Ref : Pharmaceutics , 14 : , 2022
Abstract : Chitosan-decorated liposomes were proposed for the first time for the intranasal delivery of acetylcholinesterase (AChE) reactivator pralidoxime chloride (2-PAM) to the brain as a therapy for organophosphorus compounds (OPs) poisoning. Firstly, the chitosome composition based on phospholipids, cholesterol, chitosans (Cs) of different molecular weights, and its arginine derivative was developed and optimized. The use of the polymer modification led to an increase in the encapsulation efficiency toward rhodamine B (RhB; ~85%) and 2-PAM (~60%) by 20% compared to conventional liposomes. The formation of monodispersed and stable nanosized particles with a hydrodynamic diameter of up to 130 nm was shown using dynamic light scattering. The addition of the polymers recharged the liposome surface (from -15 mV to +20 mV), which demonstrates the successful deposition of Cs on the vesicles. In vitro spectrophotometric analysis showed a slow release of substrates (RhB and 2-PAM) from the nanocontainers, while the concentration and Cs type did not significantly affect the chitosome permeability. Flow cytometry and fluorescence microscopy qualitatively and quantitatively demonstrated the penetration of the developed chitosomes into normal Chang liver and M-HeLa cervical cancer cells. At the final stage, the ability of the formulated 2-PAM to reactivate brain AChE was assessed in a model of paraoxon-induced poisoning in an in vivo test. Intranasal administration of 2-PAM-containing chitosomes allows it to reach the degree of enzyme reactivation up to 35 +/- 4%.
ESTHER : Vasilieva_2022_Pharmaceutics_14_
PubMedSearch : Vasilieva_2022_Pharmaceutics_14_
PubMedID: 36559339

Title : Novel Uracil-Based Inhibitors of Acetylcholinesterase with Potency for Treating Memory Impairment in an Animal Model of Alzheimer's Disease - Semenov_2022_Molecules_27_
Author(s) : Semenov VE , Zueva IV , Lushchekina SV , Suleimanov EG , Gubaidullina LM , Shulaeva MM , Lenina OA , Petrov KA
Ref : Molecules , 27 : , 2022
Abstract : Novel derivatives based on 6-methyluracil and condensed uracil, 2,4-quinazoline-2,4-dione, were synthesized with terminal meta- and para-benzoate moieties in polymethylene chains at the N atoms of the pyrimidine ring. In the synthesized compounds, the polymethylene chains were varied from having tris- to hexamethylene chains and quaternary ammonium groups; varying substituents (ester, salt, acid) at benzene ring were introduced into the chains and benzoate moieties. In vivo biological experiments demonstrated the potency of these compounds in decreasing the number of beta-amyloid plaques and their suitability for the treatment of memory impairment in a transgenic model of Alzheimer's disease.
ESTHER : Semenov_2022_Molecules_27_
PubMedSearch : Semenov_2022_Molecules_27_
PubMedID: 36431954

Title : Balanced modulation of neuromuscular synaptic transmission via M1 and M2 muscarinic receptors during inhibition of cholinesterases - Lenina_2022_Sci.Rep_12_1688
Author(s) : Lenina OA , Petrov KA
Ref : Sci Rep , 12 :1688 , 2022
Abstract : Organophosphorus (OP) compounds that inhibit acetylcholinesterase are a common cause of poisoning worldwide, resulting in several hundred thousand deaths each year. The pathways activated during OP compound poisoning via overstimulation of muscarinic acetylcholine receptors (mAChRs) play a decisive role in toxidrome. The antidotal therapy includes atropine, which is a nonspecific blocker of all mAChR subtypes. Atropine is efficient for mitigating depression in respiratory control centers but does not benefit patients with OP-induced skeletal muscle weakness. By using an ex vivo model of OP-induced muscle weakness, we studied the effects of the M1/M4 mAChR antagonist pirenzepine and the M2/M4 mAChR antagonist methoctramine on the force of mouse diaphragm muscle contraction. It was shown that weakness caused by the application of paraoxon can be significantly prevented by methoctramine (1 microM). However, neither pirenzepine (0.1 microM) nor atropine (1 microM) was able to prevent muscle weakness. Moreover, the application of pirenzepine significantly reduced the positive effect of methoctramine. Thus, balanced modulation of neuromuscular synaptic transmission via M1 and M2 mAChRs contributes to paraoxon-induced muscle weakness. It was shown that methoctramine (10 micromol/kg, i.p.) and atropine (50 micromol/kg, i.p.) were equieffective toward increasing the survival of mice poisoned with a 2xLD(50) dose of paraoxon.
ESTHER : Lenina_2022_Sci.Rep_12_1688
PubMedSearch : Lenina_2022_Sci.Rep_12_1688
PubMedID: 35105922

Title : Novel slow-binding reversible acetylcholinesterase inhibitors based on uracil moieties for possible treatment of myasthenia gravis and protection from organophosphate poisoning - Saifina_2022_Eur.J.Med.Chem_246_114949
Author(s) : Saifina LF , Abdalla M , Gubaidullina LM , Zueva IV , Eltayb WA , El-Arabey AA , Kharlamova AD , Lenina OA , Semenov VE , Petrov KA
Ref : Eur Journal of Medicinal Chemistry , 246 :114949 , 2022
Abstract : A series of new compounds in which uracil and 3,6-dimethyluracil moieties are bridged with different spacers were prepared and evaluated in vitro for the acetyl- and butyrylcholinesterase (AChE and BChE) inhibitory activities. These bisuracils are shown to be very effective inhibitors of AChE, inhibiting the enzyme at nano- and lower molar concentrations with extremely high selectivity for AChE vs. BChE. Kinetic analysis showed that the lead compound 2h acts as a slow-binding inhibitor of AChE and possess a long drug-target residence time (tau = 1/k(off) = 18.6 +/- 7.5smin). Moreover, compound 2h ameliorated muscle weakness in myasthenia gravis rat model with a lower effective dose and longer lasting effect than pyridostigmine bromide. Besides, it was shown that compound 2h has an effect of increasing efficiency of antidotal therapy as a pretreatment for poisoning by organophosphates.
ESTHER : Saifina_2022_Eur.J.Med.Chem_246_114949
PubMedSearch : Saifina_2022_Eur.J.Med.Chem_246_114949
PubMedID: 36462442

Title : Cholinesterases in Tripartite Neuromuscular Synapse - Petrov_2021_Front.Mol.Neurosci_14_811220
Author(s) : Petrov KA , Proskurina SE , Krejci E
Ref : Front Mol Neurosci , 14 :811220 , 2021
Abstract : The neuromuscular junction (NMJ) is a tripartite synapse in which not only presynaptic and post-synaptic cells participate in synaptic transmission, but also terminal Schwann cells (TSC). Acetylcholine (ACh) is the neurotransmitter that mediates the signal between the motor neuron and the muscle but also between the motor neuron and TSC. ACh action is terminated by acetylcholinesterase (AChE), anchored by collagen Q (ColQ) in the basal lamina of NMJs. AChE is also anchored by a proline-rich membrane anchor (PRiMA) to the surface of the nerve terminal. Butyrylcholinesterase (BChE), a second cholinesterase, is abundant on TSC and anchored by PRiMA to its plasma membrane. Genetic studies in mice have revealed different regulations of synaptic transmission that depend on ACh spillover. One of the strongest is a depression of ACh release that depends on the activation of alpha7 nicotinic acetylcholine receptors (nAChR). Partial AChE deficiency has been described in many pathologies or during treatment with cholinesterase inhibitors. In addition to changing the activation of muscle nAChR, AChE deficiency results in an ACh spillover that changes TSC signaling. In this mini-review, we will first briefly outline the organization of the NMJ. This will be followed by a look at the role of TSC in synaptic transmission. Finally, we will review the pathological conditions where there is evidence of decreased AChE activity.
ESTHER : Petrov_2021_Front.Mol.Neurosci_14_811220
PubMedSearch : Petrov_2021_Front.Mol.Neurosci_14_811220
PubMedID: 35002624

Title : Protective effects of m-(tert-butyl) trifluoroacetophenone, a transition state analogue of acetylcholine, against paraoxon toxicity and memory impairments - Zueva_2021_Chem.Biol.Interact_345_109558
Author(s) : Zueva IV , Lenina OA , Kayumova RM , Petrov KA , Masson P
Ref : Chemico-Biological Interactions , 345 :109558 , 2021
Abstract : m-(Tert-butyl) trifluoroacetophenone (TFK), a slow-binding inhibitor of acetylcholinesterase (AChE), a transition state analog of acetylcholine, was investigated as a potential neuroprotectant of central and peripheral AChE against organophosphate paraoxon (POX) toxicity. Acute toxicity and pharmacological effects of TFK were investigated on mice and rats. Intraperitoneal administered TFK has low acute toxicity in mice (LD(50) = 19 mg/kg). Effects on motor function as investigated by rotarod and open field tests showed that TFK up to 5 mg/kg did not alter motor coordination and stereotypical exploration behavior of mice. Passive avoidance test showed that 1 or 5 mg/kg TFK restored memory impairment in scopolamine-induced Alzheimer's disease-like dementia in rats. Pretreatment of mice with 5 mg/kg TFK, 2-3 hrs before challenge by 2xLD(50) POX provided a modest and short protection against POX toxicity. Futhermore, analysis of POX-induced neuronal degeneration by using fluoro-jade B staining showed that TFK pretreatment, at the dose 5mg/kg before POX challenge, significantly reduced the density of apoptotic cells in hippocampus and entorhinal cortex of mice. Thus, TFK is capable of reducing POX-induced neurotoxicity.
ESTHER : Zueva_2021_Chem.Biol.Interact_345_109558
PubMedSearch : Zueva_2021_Chem.Biol.Interact_345_109558
PubMedID: 34147486

Title : Novel Acetylcholinesterase Inhibitors Based on Uracil Moiety for Possible Treatment of Alzheimer Disease - Semenov_2020_Molecules_25_
Author(s) : Semenov VE , Zueva IV , Mukhamedyarov MA , Lushchekina SV , Petukhova EO , Gubaidullina LM , Krylova ES , Saifina LF , Lenina OA , Petrov KA
Ref : Molecules , 25 : , 2020
Abstract : In this study, novel derivatives based on 6-methyluracil and condensed uracil were synthesized, namely, 2,4-quinazoline-2,4-dione with w-(ortho-nitrilebenzylethylamino) alkyl chains at the N atoms of the pyrimidine ring. In this series of synthesized compounds, the polymethylene chains were varied from having tetra- to hexamethylene chains, and secondary NH, tertiary ethylamino, and quaternary ammonium groups were introduced into the chains. The molecular modeling of the compounds indicated that they could function as dual binding site acetylcholinesterase inhibitors, binding to both the peripheral anionic site and active site. The data from in vitro experiments show that the most active compounds exhibit affinity toward acetylcholinesterase within a nanomolar range, with selectivity for acetylcholinesterase over butyrylcholinesterase reaching four orders of magnitude. In vivo biological assays demonstrated the potency of these compounds in the treatment of memory impairment using an animal model of Alzheimer disease.
ESTHER : Semenov_2020_Molecules_25_
PubMedSearch : Semenov_2020_Molecules_25_
PubMedID: 32932702

Title : Biomedical potentialities of cationic geminis as modulating agents of liposome in drug delivery across biological barriers and cellular uptake - Pavlov_2020_Int.J.Pharm__119640
Author(s) : Pavlov RV , Gaynanova GA , Kuznetsova DA , Vasileva LA , Zueva IV , Sapunova AS , Buzyurova DN , Babaev VM , Voloshina AD , Lukashenko SS , Kh Rizvanov I , Petrov KA , Ya Zakharova L , Sinyashin OG
Ref : Int J Pharm , :119640 , 2020
Abstract : Hydroxyethyl bearing gemini surfactants, alkanediyl-alpha,w-bis(N-hexadecyl-N-2-hydroxyethyl-N-methylammonium bromide), 16-s-16(OH), were used to augment phosphatidylcholine based liposomes to achieve higher stability and enhanced cellular uptake and penetration. The developed liposomes were loaded with rhodamine B, doxorubicin hydrochloride, pralidoxime chloride to investigate release properties, cytotoxicity in vitro, as well as ability to cross the blood-brain barrier. At molar ratios of 35:1 (lipid:surfactant) the formulation was found to be of low toxicity, stable for two months, and able to deliver rhodamine B beyond the blood-brain barrier in rats. In vivo, pharmacokinetics of free and formulated 2-PAM in plasma and brain were evaluated, liposomal 2-PAM was found to reactivate 27% of brain acetylcholinesterase, which is, to our knowledge, the first example of such high degree of reactivation after intravenous administration of liposomal drug.
ESTHER : Pavlov_2020_Int.J.Pharm__119640
PubMedSearch : Pavlov_2020_Int.J.Pharm__119640
PubMedID: 32673770

Title : Surface modification of pralidoxime chloride-loaded solid lipid nanoparticles for enhanced brain reactivation of organophosphorus-inhibited AChE: pharmacokinetics in rat - Buzyurova_2020_Toxicology__152578
Author(s) : Buzyurova DN , Pashirova TN , Zueva IV , Burilova EA , Shaihutdinova ZM , Rizvanov IK , Babaev VM , Petrov KA , Souto EB
Ref : Toxicology , :152578 , 2020
Abstract : The nanotechnological approach is an innovative strategy of high potential to achieve reactivation of organophosphorus-inhibited acetylcholinesterase in central nervous system. It was previously shown that pralidoxime chloride-loaded solid lipid nanoparticles (2-PAM-SLNs) are able to protect the brain against pesticide (paraoxon) central toxicity. In the present work, we increased brain AChE reactivation efficacy by PEGylation of 2-PAM-SLNs using PEG-lipid N-(carbonyl-methoxypolyethylene glycol-2000)-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, sodium salt) (DSPE-PEG(2000)) as a surface-modifier of SLNs. To perform pharmacokinetic study, a simple, sensitive (LLOQ 1.0 ng/ml) high-performance liquid chromatography tandem mass spectrometry with atmospheric pressure chemical ionization by multiple reaction monitoring mode (HPLC-APCI-MS) was developed. The method was compared to mass spectrometry with electrospray ionization. The method was validated for linearity, accuracy, precision, extraction recovery, matrix effect and stability. Acetophenone oxime was used as the internal standard for the quantification of 2-PAM in rat plasma and brain tissue after intravenous administration. 2-PAM-DSPE-PEG(2000)-SLNs of mean size about 80 nm (PDI = 0.26), zeta-potential of -55 mV and of high in vitro stability, prolonged the elimination phase of 2-PAM from the bloodstream more than 3 times compared to free 2-PAM. An increase in reactivation of POX-inhibited human brain acetylcholinesterase up to 36.08 +/- 4.3% after intravenous administration of 2-PAM-DSPE-PEG(2000)-SLNs (dose of 2-PAM is 5 mg/kg) was achieved. The result is one of the first examples where this level of brain acetylcholinesterase reactivation was achieved. Thus, the implementation of different approaches for targeting and modifying nanoparticles' surface gives hope for improving the antidotal treatment of organophosphorus poisoning by marketed reactivators.
ESTHER : Buzyurova_2020_Toxicology__152578
PubMedSearch : Buzyurova_2020_Toxicology__152578
PubMedID: 32898602

Title : Slow-binding reversible inhibitor of acetylcholinesterase with long-lasting action for prophylaxis of organophosphate poisoning - Lenina_2020_Sci.Rep_10_16611
Author(s) : Lenina OA , Zueva IV , Zobov VV , Semenov VE , Masson P , Petrov KA
Ref : Sci Rep , 10 :16611 , 2020
Abstract : Organophosphorus (OP) compounds represent a serious health hazard worldwide. The dominant mechanism of their action results from covalent inhibition of acetylcholinesterase (AChE). Standard therapy of acute OP poisoning is partially effective. However, prophylactic administration of reversible or pseudo-irreversible AChE inhibitors before OP exposure increases the efficiency of standard therapy. The purpose of the study was to test the duration of the protective effect of a slow-binding reversible AChE inhibitor (C547) in a mouse model against acute exposure to paraoxon (POX). It was shown that the rate of inhibition of AChE by POX in vitro after pre-inhibition with C547 was several times lower than without C547. Ex vivo pre-incubation of mouse diaphragm with C547 significantly prevented the POX-induced muscle weakness. Then it was shown that pre-treatment of mice with C547 at the dose of 0.01 mg/kg significantly increased survival after poisoning by 2xLD(50) POX. The duration of the pre-treatment was effective up to 96 h, whereas currently used drug for pre-exposure treatment, pyridostigmine at a dose of 0.15 mg/kg was effective less than 24 h. Thus, long-lasting slow-binding reversible AChE inhibitors can be considered as new potential drugs to increase the duration of pre-exposure treatment of OP poisoning.
ESTHER : Lenina_2020_Sci.Rep_10_16611
PubMedSearch : Lenina_2020_Sci.Rep_10_16611
PubMedID: 33024231

Title : Bi-functional sterically hindered phenol lipid-based delivery systems as potential multi-target agents against Alzheimer's disease via an intranasal route - Burilova_2020_Nanoscale_12_13757
Author(s) : Burilova EA , Pashirova TN , Zueva IV , Gibadullina EM , Lushchekina SV , Sapunova AS , Kayumova RM , Rogov AM , Evtjugin VG , Sudakov IA , Vyshtakalyuk AB , Voloshina AD , Bukharov SV , Burilov AR , Petrov KA , Zakharova LY , Sinyashin OG
Ref : Nanoscale , 12 :13757 , 2020
Abstract : New lipid-based nanomaterials and multi-target directed ligands (MTDLs) based on sterically hindered phenol, containing a quaternary ammonium moiety (SHP-s-R, with s = 2,3) of varying hydrophobicity (R = CH2Ph and CnH2n+1, with n = 8, 10, 12, 16), have been prepared as potential drugs against Alzheimer's disease (AD). SHP-s-R are inhibitors of human cholinesterases with antioxidant properties. The inhibitory potency of SHP-s-R and selectivity ratio of cholinesterase inhibition were found to significantly depend on the length of the methylene spacer (s) and alkyl chain length. The compound SHP-2-16 showed the best IC50 for human AChE and the highest selectivity, being 30-fold more potent than for human BChE. Molecular modeling of SHP-2-16 binding to human AChE suggests that this compound is a dual binding site inhibitor that interacts with both the peripheral anionic site and catalytic active site. The relationship between self-assembly parameters (CMC, solubilization capacity, aggregation number), antioxidant activity and a toxicological parameter (hemolytic action on human red blood cells) was investigated. Two sterically hindered phenols (SHP-2-Bn and SHP-2-R) were loaded into L-alpha-phosphatidylcholine (PC) nanoparticles by varying the SHP alkyl chain length. For the brain AChE inhibition assay, PC/SHP-2-Bn/SHP-2-16 nanoparticles were administered to rats intranasally at a dose of 8 mg kg-1. The Morris water maze experiment showed that scopolamine-induced AD-like dementia in rats treated with PC/SHP-2-Bn/SHP-2-16 nanoparticles was significantly reduced. This is the first example of cationic SHP-phospholipid nanoparticles for inhibition of brain cholinesterases realized by the use of intranasal administration. This route has promising potential for the treatment of AD.
ESTHER : Burilova_2020_Nanoscale_12_13757
PubMedSearch : Burilova_2020_Nanoscale_12_13757
PubMedID: 32573587

Title : Delivery nanosystems based on sterically hindered phenol derivatives containing a quaternary ammonium moiety: Synthesis, cholinesterase inhibition and antioxidant activity - Pashirova_2019_Chem.Biol.Interact_13ChEPon_310_108753
Author(s) : Pashirova TN , Burilova EA , Tagasheva RG , Zueva IV , Gibadullina EM , Nizameev IR , Sudakov IA , Vishtakalyk AB , Voloshina AD , Kadirov MK , Petrov KA , Burilov AR , Bukharov SV , Zakharova LY
Ref : Chemico-Biological Interactions , :108753 , 2019
Abstract : Multitarget ligands (MTL) based on sterically hindered phenol and containing a quaternary ammonium moiety (SHP-n-Q) were synthesized. These compounds are inhibitors of cholinesterases with antioxidant properties. The inhibitory selectivity is 10-fold potent for BChE than for AChE. IC50 of SHP-n-Q for BChE is 20muM. SHP-n-Q and their nanosystems exhibit more pronounced antioxidant properties than the synthetic antioxidant (hindered phenol, butylated hydroxytoluene). These compounds display a low hemolytic activity against human red blood cells. The nanotechnological approach was used to increase the bioavailability of SHP-n-Q derivatives. For water soluble SHP-n-Q derivative, the self-assembled structures have a size close to 100nmat critical association concentration (0.01M). Mixed cationic liposomes based on l-alpha-phosphatidylcholine and SHP-n-Q of 100nm diameter were prepared. The stability, encapsulation efficacy and release from liposomes of a model drug, Rhodamine B, depend on the structure of SHP-n-Q. Cationic liposomes based on l-alpha-phosphatidylcholine and SHP-3-Q show a good stability in time (1year) and a sustained release (>65h). They are promising templates for the development of anti-Alzheimer MT-drug delivery systems.
ESTHER : Pashirova_2019_Chem.Biol.Interact_13ChEPon_310_108753
PubMedSearch : Pashirova_2019_Chem.Biol.Interact_13ChEPon_310_108753
PubMedID: 31319075

Title : 6-Methyluracil derivatives as peripheral site ligand-hydroxamic acid conjugates: Reactivation for paraoxon-inhibited acetylcholinesterase - Semenov_2019_Eur.J.Med.Chem_185_111787
Author(s) : Semenov VE , Zueva IV , Lushchekina SV , Lenina OA , Gubaidullina LM , Saifina LF , Shulaeva MM , Kayumova RM , Saifina AF , Gubaidullin AT , Kondrashova SA , Latypov SK , Masson P , Petrov KA
Ref : Eur Journal of Medicinal Chemistry , 185 :111787 , 2019
Abstract : New uncharged conjugates of 6-methyluracil derivatives with imidazole-2-aldoxime and 1,2,4-triazole-3-hydroxamic acid units were synthesized and studied as reactivators of organophosphate-inhibited cholinesterase. Using paraoxon (POX) as a model organophosphate, it was shown that 6-methyluracil derivatives linked with hydroxamic acid are able to reactivate POX-inhibited human acetylcholinesterase (AChE) in vitro. The reactivating efficacy of one compound (5b) is lower than that of pyridinium-2-aldoxime (2-PAM). Meanwhile, unlike 2-PAM, in vivo study showed that the lead compound 5b is able: (1) to reactivate POX-inhibited AChE in the brain; (2) to decrease death of neurons and, (3) to prevent memory impairment in rat model of POX-induced neurodegeneration.
ESTHER : Semenov_2019_Eur.J.Med.Chem_185_111787
PubMedSearch : Semenov_2019_Eur.J.Med.Chem_185_111787
PubMedID: 31675511

Title : Water-soluble betaines and amines based on thiacalix[4]arene scaffold as new cholinesterase inhibitors - Padnya_2019_Bioorg.Chem__103455
Author(s) : Padnya PL , Bayarashov EE , Zueva IV , Lushchekina SV , Lenina OA , Evtugyn VG , Osin YN , Petrov KA , Stoikov, II
Ref : Bioorg Chem , :103455 , 2019
Abstract : Novel ammonium and betaine derivatives of p-tert-butylthiacalix[4]arene in cone and 1,3-alternate conformation were synthesized with high yields for the first time. The obtained compounds form in water spherical nanoparticles. It was shown by molecular docking calculations and in vitro experiments that amino and betaine derivatives can inhibit acetylcholinesterase and butyrylcholinesterase on the level of pyridostigmine while the toxicity of the obtained compounds is much lower than that of pyridostigmine.
ESTHER : Padnya_2019_Bioorg.Chem__103455
PubMedSearch : Padnya_2019_Bioorg.Chem__103455
PubMedID: 31791680

Title : New evidence for dual binding site inhibitors of acetylcholinesterase as improved drugs for treatment of Alzheimer's disease - Zueva_2019_Neuropharmacol_155_131
Author(s) : Zueva IV , Dias J , Lushchekina SV , Semenov VE , Mukhamedyarov MA , Pashirova TN , Babaev VM , Nachon F , Petrova N , Nurullin LF , Zakharova LY , Ilyin VI , Masson P , Petrov KA
Ref : Neuropharmacology , 155 :131 , 2019
Abstract : Profound synaptic dysfunction contributes to early loss of short-term memory in Alzheimer's disease. This study was set up to analyze possible neuroprotective effects of two dual binding site inhibitors of acetylcholinesterase (AChE), a new 6-methyluracil derivative, C-35, and the clinically used inhibitor donepezil. Crystal structure of the complex between human AChE and C-35 revealed tight contacts of ligand along the enzyme active site gorge. Molecular dynamics simulations indicated that the external flexible part of the ligand establishes multiple transient interactions with the enzyme peripheral anionic site. Thus, C-35 is a dual binding site inhibitor of AChE. In transgenic mice, expressing a chimeric mouse/human amyloid precursor protein and a human presenilin-1 mutant, C-35 (5mg/kg, i.p) and donepezil (0.75mg/kg, i.p) partially reversed synapse loss, decreased the number of amyloid plaques, and restored learning and memory. To separate temporal symptomatic therapeutic effects, associated with the increased lifetime of acetylcholine in the brain, from possible disease-modifying effect, an experimental protocol based on drug withdrawal from therapy was performed. When administration of C-35 and donepezil was terminated three weeks after the trial started, animals that were receiving C-35 showed a much better ability to learn than those who received vehicle or donepezil. Our results provide additional evidence that dual binding site inhibitors of AChE have Alzheimer's disease-modifying action.
ESTHER : Zueva_2019_Neuropharmacol_155_131
PubMedSearch : Zueva_2019_Neuropharmacol_155_131
PubMedID: 31132435
Gene_locus related to this paper: human-ACHE

Title : Combination delivery of two oxime-loaded lipid nanoparticles: Time-dependent additive action for prolonged rat brain protection - Pashirova_2018_J.Control.Release_290_102
Author(s) : Pashirova TN , Braiki A , Zueva IV , Petrov KA , Babaev VM , Burilova EA , Samarkina DA , Rizvanov IK , Souto EB , Jean L , Renard PY , Masson P , Zakharova LY , Sinyashin OG
Ref : J Control Release , 290 :102 , 2018
Abstract : A novel approach for brain protection against poisoning by organophosphorus agents is developed based on the combination treatment of dual delivery of two oximes. Pralidoxime chloride (2-PAM) and a novel reactivator, 6-(5-(6,7-dimethoxy-3,4-dihydroisoquinolin-2(1H)-yl)pentyl)-3-hydroxy picolinaldehyde oxime (3-HPA), have been loaded in solid-lipid nanoparticles (SLNs) to offer distinct release profile and systemic half-life for both oximes. To increase the therapeutic time window of both oximes, SLNs with two different compartments were designed to load each respective drug. Oxime-loaded SLNs of hydrodynamic diameter between 100 and 160nm and negative zeta potential (-30 to -25mV) were stable for a period of 10months at 4 degrees C. SLNs displayed longer circulation time in the bloodstream compared to free 3-HPA and free 2-PAM. Oxime-loaded SLNs were suitable for intravenous (iv) administration. Paraoxon-poisoned rats (0.8xLD50) were treated with 3-HPA-loaded SLNs and 2-PAM+3-HPA-loaded SLNs at the dose of 3-HPA and 2-PAM of 5mg/kg. Brain AChE reactivation up to 30% was slowly achieved in 5h after administration of 3-HPA-SLNs. For combination therapy with two oximes, a time-dependent additivity and increased reactivation up to 35% were observed.
ESTHER : Pashirova_2018_J.Control.Release_290_102
PubMedSearch : Pashirova_2018_J.Control.Release_290_102
PubMedID: 30308259

Title : Targeted Nanoparticles for Selective Marking of Neuromuscular Junctions and ex Vivo Monitoring of Endogenous Acetylcholine Hydrolysis - Mukhametshina_2018_ACS.Appl.Mater.Interfaces_10_14948
Author(s) : Mukhametshina AR , Fedorenko SV , Petrov AM , Zakyrjanova GF , Petrov KA , Nurullin LF , Nizameev IR , Mustafina AR , Sinyashin OG
Ref : ACS Appl Mater Interfaces , 10 :14948 , 2018
Abstract : The present work for the first time introduces nanosensors for luminescent monitoring of acetylcholinesterase (AChE)-catalyzed hydrolysis of endogenous acetylcholine (ACh) released in neuromuscular junctions of isolated muscles. The sensing function results from the quenching of Tb(III)-centered luminescence due to proton-induced degradation of luminescent Tb(III) complexes doped into silica nanoparticles (SNs, 23 nm), when acetic acid is produced from the enzymatic hydrolysis of ACh. The targeting of the silica nanoparticles by alpha-bungarotoxin was used for selective staining of the synaptic space in the isolated muscles by the nanosensors. The targeting procedure was optimized for the high sensing sensitivity. The measuring of the Tb(III)-centered luminescence intensity of the targeted SNs by fluorescent microscopy enables us to sense a release of endogenous ACh in neuromuscular junctions of the isolated muscles under their stimulation by a high-frequency train (20 Hz, for 3 min). The ability of the targeted SNs to sense an inhibiting effect of paraoxon on enzymatic activity of AChE in ex vivo conditions provides a way of mimicking external stimuli effects on enzymatic processes in the isolated muscles.
ESTHER : Mukhametshina_2018_ACS.Appl.Mater.Interfaces_10_14948
PubMedSearch : Mukhametshina_2018_ACS.Appl.Mater.Interfaces_10_14948
PubMedID: 29652477

Title : C-547, a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase: Pharmacokinetic and pharmacodynamic studies - Petrov_2018_Neuropharmacol_131_304
Author(s) : Petrov KA , Zueva IV , Kovyazina IV , Sedov I , Lushchekina SV , Kharlamova AD , Lenina O , Koshkin S , Shtyrlin Y , Nikolsky EE , Masson P
Ref : Neuropharmacology , 131 :304 , 2018
Abstract : C-547, a potent slow-binding inhibitor of acetylcholinesterase (AChE) was intravenously administered to rat (0.05mg/kg). Pharmacokinetic profiles were determined in blood and different organs: extensor digitorum longus muscle, heart, liver, lungs and kidneys as a function of time. Pharmacokinetics (PK) was studied using non-compartmental and compartmental analyses. A 3-compartment model describes PK in blood. Most of injected C-547 binds to albumin in the bloodstream. The steady-state volume of distribution (3800ml/kg) is 15 times larger than the distribution volume, indicating a good tissue distribution. C-547 is slowly eliminated (kel=0.17 h(-1); T1/2=4h) from the bloodstream. Effect of C-547 on animal model of myasthenia gravis persists for more than 72h, even though the drug is not analytically detectable in the blood. A PK/PD model was built to account for such a pharmacodynamical (PD) effect. Long-lasting effect results from micro-PD mechanisms: the slow-binding nature of inhibition, high affinity for AChE and long residence time on target at neuromuscular junction (NMJ). In addition, NMJ spatial constraints i.e. high concentration of AChE in a small volume, and slow diffusion rate of free C-547 out of NMJ, make possible effective rebinding of ligand. Thus, compared to other cholinesterase inhibitors used for palliative treatment of myasthenia gravis, C-547 is the most selective drug, displays a slow pharmacokinetics, and has the longest duration of action. This makes C-547 a promising drug leader for treatment of myasthenia gravis, and a template for development of other drugs against neurological diseases and for neuroprotection.
ESTHER : Petrov_2018_Neuropharmacol_131_304
PubMedSearch : Petrov_2018_Neuropharmacol_131_304
PubMedID: 29277489

Title : Luminescent nanoparticles for rapid monitoring of endogenous acetylcholine release in mice atria - Mukhametshina_2018_Luminescence_33_588
Author(s) : Mukhametshina A , Petrov A , Fedorenko S , Petrov KA , Nizameev I , Mustafina A , Sinyashin O
Ref : Luminescence , 33 :588 , 2018
Abstract : The present work introduces for the first time a nanoparticulate approach for ex vivo monitoring of acetylcholinesterase-catalyzed hydrolysis of endogenous acetylcholine released from nerve varicosities in mice atria. Amino-modified 20-nm size silica nanoparticles (SNs) doped by luminescent Tb(III) complexes were applied as the nanosensors. Their sensing capacity results from the decreased intensity of Tb(III)-centred luminescence due to the quenching effect of acetic acid derived from acetylcholinesterase-catalyzed hydrolysis of acetylcholine. Sensitivity of the SNs in monitoring acetylcholine hydrolysis was confirmed by in vitro experiments. Isolated atria were exposed to the nanosensors for 10 min to stain cell membranes. Acetylcholine hydrolysis was monitored optically in the atria samples by measuring quenching of Tb(III)-centred luminescence by acetic acid derived from endogenous acetylcholine due to its acetylcholinesterase-catalyzed hydrolysis. The reliability of the sensing was demonstrated by the quenching effect of exogenous acetylcholine added to the bath solution. Additionally, no luminescence quenching occurred when the atria were pre-treated with the acetylcholinesterase inhibitor paraoxon.
ESTHER : Mukhametshina_2018_Luminescence_33_588
PubMedSearch : Mukhametshina_2018_Luminescence_33_588
PubMedID: 29377578

Title : Specific inhibition of acetylcholinesterase as an approach to decrease muscarinic side effects during myasthenia gravis treatment - Petrov_2018_Sci.Rep_8_304
Author(s) : Petrov KA , Kharlamova AD , Lenina OA , Nurtdinov AR , Sitdykova ME , Ilyin VI , Zueva IV , Nikolsky EE
Ref : Sci Rep , 8 :304 , 2018
Abstract : Non-selective inhibitors of cholinesterases (ChEs) are clinically used for treatment of myasthenia gravis (MG). While being generally safe, they cause numerous adverse effects including induction of hyperactivity of urinary bladder and intestines affecting quality of patients life. In this study we have compared two ChEs inhibitors, a newly synthesized compound C547 and clinically used pyridostigmine bromide, by their efficiency to reduce muscle weakness symptoms and ability to activate contractions of urinary bladder in a rat model of autoimmune MG. We found that at dose effectively reducing MG symptoms, C547 did not affect activity of rat urinary bladder. In contrast, at equipotent dose, pyridostigmine caused a significant increase in tonus and force of spontaneous contractions of bladder wall. We also found that this profile of ChEs inhibitors translates into the preparation of human urinary bladder. The difference in action observed for C547 and pyridostigmine we attribute to a high level of pharmacological selectivity of C547 in inhibiting acetylcholinesterase as compared to butyrylcholinesterase. These results raise reasonable hope that selective acetylcholinesterase inhibitors should show efficacy in treating MG in human patients with a significant reduction in adverse effects related to hyperactivation of smooth muscles.
ESTHER : Petrov_2018_Sci.Rep_8_304
PubMedSearch : Petrov_2018_Sci.Rep_8_304
PubMedID: 29321572

Title : Mixed cationic liposomes for brain delivery of drugs by the intranasal route: The acetylcholinesterase reactivator 2-PAM as encapsulated drug model - Pashirova_2018_Colloids.Surf.B.Biointerfaces_171_358
Author(s) : Pashirova TN , Zueva IV , Petrov KA , Lukashenko SS , Nizameev IR , Kulik NV , Voloshina AD , Almasy L , Kadirov MK , Masson P , Souto EB , Zakharova LY , Sinyashin OG
Ref : Colloids Surf B Biointerfaces , 171 :358 , 2018
Abstract : New mixed cationic liposomes based on L-alpha-phosphatidylcholine and dihexadecylmethylhydroxyethylammonium bromide (DHDHAB) were designed to overcome the BBB crossing by using the intranasal route. Synthesis and self-assembly of DHDHAB were performed. A low critical association concentration (0.01 mM), good solubilization properties toward hydrophobic dye Orange OT and antimicrobial activity against gram-positive bacteria Staphylococcus aureus (MIC=7.8 mug mL(-1)) and Bacillus cereus (MIC=7.8 mug mL(-1)), low hemolytic activities against human red blood cells (less than 10%) were achieved. Conditions for preparation of cationic vesicles and mixed liposomes with excellent colloidal stability at room temperature were determined. The intranasal administration of rhodamine B-loaded cationic liposomes was shown to increase bioavailability into the brain in comparison to the intravenous injection. The cholinesterase reactivator, 2-PAM, was used as model drug for the loading in cationic liposomes. 2-PAM-loaded cationic liposomes displayed high encapsulation efficiency ( approximately 90%) and hydrodynamic diameter close to 100 nm. Intranasally administered 2-PAM-loaded cationic liposomes were effective against paraoxon-induced acetylcholinesterase inhibition in the brain. 2-PAM-loaded liposomes reactivated 12 +/- 1% of brain acetylcholinesterase. This promising result opens the possibility to use marketed positively charged oximes in medical countermeasures against organophosphorus poisoning for reactivation of central acetylcholinesterase by implementing a non-invasive approach, via the "nose-brain" pathway.
ESTHER : Pashirova_2018_Colloids.Surf.B.Biointerfaces_171_358
PubMedSearch : Pashirova_2018_Colloids.Surf.B.Biointerfaces_171_358
PubMedID: 30059851

Title : Autoregulation of Acetylcholine Release and Micro-Pharmacodynamic Mechanisms at Neuromuscular Junction: Selective Acetylcholinesterase Inhibitors for Therapy of Myasthenic Syndromes - Petrov_2018_Front.Pharmacol_9_766
Author(s) : Petrov KA , Nikolsky EE , Masson P
Ref : Front Pharmacol , 9 :766 , 2018
Abstract : Neuromuscular junctions (NMJs) are directly involved into such indispensable to life processes as respiration and locomotion. However, motor nerve forms only one synaptic contact at each muscle fiber. This unique configuration requires specific properties and constrains to be effective. The very high density of acetylcholine receptors (AChRs) of muscle type in synaptic cleft and an excess of acetylcholine (ACh) released under physiological conditions make this synapse extremely reliable. Nevertheless, under pathological conditions such as myasthenia gravis and congenital myasthenic syndromes, the safety factor can be markedly reduced. Drugs used for short-term symptomatic therapy of these pathological states, cause partial inhibition of cholinesterases (ChEs). These enzymes catalyze the hydrolysis of ACh, thus terminate its action on AChRs. Extension of the lifetime of ACh molecules compensates muscular AChRs abnormalities and, consequently, rescues muscle contractions. In this mini review, we will first outline the functional organization of the NMJ, and then, consider the concept of the safety factor and how it may be changed. This will be followed by a look at autoregulation of ACh release that influences the safety factor of NMJs. Finally, we will consider the morphological features of NMJs as a putative reserve to increase effectiveness of pathological muscle weakness therapy by ChEs inhibitors due to opportunity to use micro-pharmacodynamic mechanisms.
ESTHER : Petrov_2018_Front.Pharmacol_9_766
PubMedSearch : Petrov_2018_Front.Pharmacol_9_766
PubMedID: 30050445

Title : Nanoparticle-Delivered 2-PAM for Rat Brain Protection against Paraoxon Central Toxicity - Pashirova_2017_ACS.Appl.Mater.Interfaces_9_16922
Author(s) : Pashirova TN , Zueva IV , Petrov KA , Babaev VM , Lukashenko SS , Rizvanov IK , Souto EB , Nikolsky EE , Zakharova LY , Masson P , Sinyashin OG
Ref : ACS Appl Mater Interfaces , 9 :16922 , 2017
Abstract : Solid lipid nanoparticles (SLNs) are among the most promising nanocarriers to target the blood-brain barrier (BBB) for drug delivery to the central nervous system (CNS). Encapsulation of the acetylcholinesterase reactivator, pralidoxime chloride (2-PAM), in SLNs appears to be a suitable strategy for protection against poisoning by organophosphorus agents (OPs) and postexposure treatment. 2-PAM-loaded SLNs were developed for brain targeting and delivery via intravenous (iv) administration. 2-PAM-SLNs displayed a high 2-PAM encapsulation efficiency ( approximately 90%) and loading capacity (maximum 30.8 +/- 1%). Drug-loaded particles had a mean hydrodynamic diameter close to 100 nm and high negative zeta potential (-54 to -15 mV). These properties contribute to improve long-term stability of 2-PAM-SLNs when stored both at room temperature (22 degrees C) and at 4 degrees C, as well as to longer circulation time in the bloodstream compared to free 2-PAM. Paraoxon-poisoned rats (2 x LD50) were treated with 2-PAM-loaded SLNs at a dose of 2-PAM of 5 mg/kg. 2-PAM-SLNs reactivated 15% of brain AChE activity. Our results confirm the potential use of SLNs loaded with positively charged oximes as a medical countermeasure both for protection against OPs poisoning and for postexposure treatment.
ESTHER : Pashirova_2017_ACS.Appl.Mater.Interfaces_9_16922
PubMedSearch : Pashirova_2017_ACS.Appl.Mater.Interfaces_9_16922
PubMedID: 28504886

Title : Sensing activity of cholinesterases through a luminescence response of the hexarhenium cluster complex [{Re6S8}(OH)6](4.) - Elistratova_2016_Analyst_141_4204
Author(s) : Elistratova JG , Mustafina AR , Brylev KA , Petrov KA , Shestopalov MA , Mironov YV , Babaev VM , Rizvanov IK , Masson P , Sinyashin OG
Ref : Analyst , 141 :4204 , 2016
Abstract : The present work describes a new method to sense cholinesterase-catalyzed hydrolysis of acetylcholine (ACh) through a luminescence response of the hexarhenium cluster complex [{Re6S8}(OH)6](4-). A proton released from acetylcholinesterase (AChE)- or butyrylcholinesterase (BuChE)-catalyzed hydrolysis of ACh results in time-resolved sensitization of cluster-centered luminescence. The sensitization results from protonation of apical hydroxo-groups of the cluster complex. The protonation is affected by a counter ion effect. Thus, optimal conditions for adequate sensing of acetic acid produced by ACh hydrolysis are highlighted. Time-resolved luminescence and pH measurements under conditions of AChE-catalyzed hydrolysis of ACh show a good correlation between the cluster-centered luminescence and pH-induced inhibition of AChE. The inhibition is not significant within the first two minutes of ACh hydrolysis. Thus, the luminescence response measured within two minutes is dependent on both substrate and enzyme concentrations, which fits with AChE and BuChE kinetics. The usability of cluster-centered luminescence for monitoring the concentration-dependent inhibition of AChE with irreversible inhibitors is demonstrated, using a carbamylating agent, pyridostigmine bromide, as a model.
ESTHER : Elistratova_2016_Analyst_141_4204
PubMedSearch : Elistratova_2016_Analyst_141_4204
PubMedID: 27169678

Title : Slow-binding inhibition of acetylcholinesterase by an alkylammonium derivative of 6-methyluracil: mechanism and possible advantages for myasthenia gravis treatment - Kharlamova_2016_Biochem.J_473_1225
Author(s) : Kharlamova AD , Lushchekina SV , Petrov KA , Kots ED , Nachon F , Villard-Wandhammer M , Zueva IV , Krejci E , Reznik VS , Zobov VV , Nikolsky EE , Masson P
Ref : Biochemical Journal , 473 :1225 , 2016
Abstract : Inhibition of human AChE (acetylcholinesterase) and BChE (butyrylcholinesterase) by an alkylammonium derivative of 6-methyluracil, C-547, a potential drug for the treatment of MG (myasthenia gravis) was studied. Kinetic analysis of AChE inhibition showed that C-547 is a slow-binding inhibitor of type B, i.e. after formation of the initial enzyme.inhibitor complex (Ki=140 pM), an induced-fit step allows establishment of the final complex (Ki*=22 pM). The estimated koff is low, 0.05 min(-1) On the other hand, reversible inhibition of human BChE is a fast-binding process of mixed-type (Ki=1.77 muM; Ki'=3.17 muM). The crystal structure of mouse AChE complexed with C-547 was solved at 3.13 A resolution. The complex is stabilized by cation-pi, stacking and hydrogen-bonding interactions. Molecular dynamics simulations of the binding/dissociation processes of C-547 and C-35 (a non-charged analogue) to mouse and human AChEs were performed. Molecular modelling on mouse and human AChE showed that the slow step results from an enzyme conformational change that allows C-547 to cross the bottleneck in the active-site gorge, followed by formation of tight complex, as observed in the crystal structure. In contrast, the related non-charged compound C-35 is not a slow-binding inhibitor. It does not cross the bottleneck because it is not sensitive to the electrostatic driving force to reach the bottom of the gorge. Thus C-547 is one of the most potent and selective reversible inhibitors of AChE with a long residence time, tau=20 min, longer than for other reversible inhibitors used in the treatment of MG. This makes C-547 a promising drug for the treatment of this disease.
ESTHER : Kharlamova_2016_Biochem.J_473_1225
PubMedSearch : Kharlamova_2016_Biochem.J_473_1225
PubMedID: 26929400
Gene_locus related to this paper: mouse-ACHE

Title : Novel potent pyridoxine-based inhibitors of AChE and BChE, structural analogs of pyridostigmine, with improved in vivo safety profile - Strelnik_2016_Bioorg.Med.Chem.Lett_26_4092
Author(s) : Strelnik AD , Petukhov AS , Zueva IV , Zobov VV , Petrov KA , Nikolsky EE , Balakin KV , Bachurin SO , Shtyrlin YG
Ref : Bioorganic & Medicinal Chemistry Lett , 26 :4092 , 2016
Abstract : We report a novel class of carbamate-type ChE inhibitors, structural analogs of pyridostigmine. A small library of congeneric pyridoxine-based compounds was designed, synthesized and evaluated for AChE and BChE enzymes inhibition in vitro. The most active compounds have potent enzyme inhibiting activity with IC50 values in the range of 0.46-2.1muM (for AChE) and 0.59-8.1muM (for BChE), with moderate selectivity for AChE comparable with that of pyridostigmine and neostigmine. Acute toxicity studies using mice models demonstrated excellent safety profile of the obtained compounds with LD50 in the range of 22-326mg/kg, while pyridostigmine and neostigmine are much more toxic (LD50 3.3 and 0.51mg/kg, respectively). The obtained results pave the way to design of novel potent and safe cholinesterase inhibitors for symptomatic treatment of neuromuscular disorders.
ESTHER : Strelnik_2016_Bioorg.Med.Chem.Lett_26_4092
PubMedSearch : Strelnik_2016_Bioorg.Med.Chem.Lett_26_4092
PubMedID: 27377327

Title : Molecular modeling of mechanism of action of anti-myasthenia gravis slow-binding inhibitor of acetylcholinesterase - Lushchekina_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S74
Author(s) : Lushchekina SV , Kots ED , Kharlamova AD , Petrov KA , Masson P
Ref : Int J Risk Saf Med , 27 Suppl 1 :S74 , 2015
Abstract : BACKGROUND: Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by fluctuating weakness of voluntary skeletal muscles. The cause of autoimmune response is unknown and only symptomatic therapies for MG are currently available. Pharmacological correction of synaptic failure underlying MG, involves partial inhibition acetyl- and butyrylcholinesterase. Effectiveness of cholinesterase inhibitors in the symptomatic treatment of MG is based on their ability to potentiate the effects of acetylcholine by decreasing the rate of its enzymatic hydrolysis at neuromuscular junctions. Several new inhibitors of AChE were tested in animal model of MG and may be considered as valuable candidates for the treatment of pathological muscle weakness syndromes. In this study, we have investigated mechanisms of ChE inhibition by one of the most active 6-methyluracil derivatives (C547), as well as the possible benefits of using this compound for MG treatment compared to traditionally used pyridostigmine bromide.It was experimentally shown that C547 is a <<pseudo-irreversible>> slow-binding inhibitor of human AChE. Human BChE is reversibly inhibited by C547 with an affinity about 4 orders of magnitude lower than that of human AChE. Slow-binding inhibition of AChE leads to a lasting (over 24 hours) effect on the symptoms of muscle weakness in animal model of MG after a single administration of C547. OBJECTIVE: The aim of the present molecular modeling study was to reveal mechanism of AChE inhibition by C547 and elucidate its apparent <<pseudo-irreversibility>>.
METHODS: Two principle methods used in the present study were molecular docking and molecular dynamics (MD). Molecular docking was performed with Autodock 4.2.6 software, Lamarckian Genetic Algorithm to obtain structure of protein inhibitor complexes and Local Search for MD snapshots to compare relative binding affinity. For MD simulations NAMD 2.10 software with Charrm 36 force field was used, for the ligand C547 Charmm General Force Field was used, and missing parameters were obtained with quantum mechanical calculations. Unconstrained MD, steered MD (SMD) and free energy calculations with adaptive biasing force were performed.
RESULTS: During unconstrained MD, C547 very rapidly binded to the peripheral anionic site (PAS) of AChE. To pass the bottleneck, application of the external force was required (SMD). Both SMD modelling and free energy calculation revealed that after crossing the AChE bottleneck, C547 falls into very favorable position. At the same time the rupture of interactions as well as overcoming the bottleneck gates in the course of pulling out procedure requires application of much higher force than during the pulling-in process. This difference between binding and dissociating processes explains apparent <<pseudo-irreversibility>> of the inhibitor.
CONCLUSIONS: These findings are in good agreement with kinetics study showing that C-547 is a slow-binding inhibitor of type B, i.e. after rapid initial binding of inhibitor, the enzyme-inhibitor complex undergoes an isomerization step. Position obtained by SMD is in good agreement with X-ray data obtained by F. Nachon, IBS, France.
ESTHER : Lushchekina_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S74
PubMedSearch : Lushchekina_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S74
PubMedID: 26639721

Title : Macrocyclic derivatives of 6-methyluracil: New ligands of the peripheral anionic site of acetylcholinesterase - Petrov_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S72
Author(s) : Petrov KA
Ref : Int J Risk Saf Med , 27 Suppl 1 :S72 , 2015
Abstract : BACKGROUND: Acetylcholinesterase (AChE) inhibitors are widely used in medicine for pharmacological correction of cholinergic neurotransmission pathologies such as myasthenia gravis (MG) and Alzheimer's disease [1, 2]. The efficacy of anti-AChE drugs is based on their ability to potentiate the effects of acetylcholine (ACh) due to a decrease in the rate of AChE-catalyzed hydrolysis of ACh. Crystallographic studies showed that the active site of AChE is located at the bottom of a deep gorge [3]. It was shown that, in addition to its catalytic center, AChE has other sites that are crucial for the proper functioning of the enzyme. In particular, the so-called peripheral anionic site (PAS) located at the entrance of the active site gorge is responsible for: 1) allosteric modulation of the catalytic center; 2) enzyme inhibition at high substrate concentration; 3) and non-catalytic functions such as enhancement of cell adhesion and neurite outgrowth. OBJECTIVE: Especially interesting is the relationship between the PAS and pathological beta-amyloid deposition. This led to a new hypothesis for rational design of more effective anti-Alzheimer drugs [4].
METHODS: Concentration of drug producing 50% of AChE activity inhibition (IC50) was measured using the method of Ellman et al. [5]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [6]. Molecular docking was performed with Autodock 4.2.6 software.
RESULTS: We described previously a new class of selective mammalian AChE vs. butyrylcholinesterase (BChE) inhibitors based on alkylammonium derivatives of 6-methyluracil of acyclic topology [7]. In the present study, taking acyclic derivatives of 6-methyluracil as a model AChE inhibitor, we attempted to develop AChE inhibitors that specifically bind to the PAS with weak binding to the active site of AChE. We attempted to increase the size of AChE ligands to restrict specific binding to the PAS of AChE. To this aim we synthesized pyrimidinophanes bearing two o-nitrobenzylethyldialkylammonium heads. Almost all of synthesized pyrimidinophanes inhibited AChE in the nanomolar range. Based on molecular docking simulations, it was suggested that compounds bind AChE to the active center as well as to the PAS or only to the PAS. Thus, we found that introduction of the spacer, flexible or rigid, between [5-(o-nitrobenzylethylammonium)pentyl] units at N atoms of the 6-methyluracil moiety allows tuning the binding of 6-methyluracil derivatives with AChE.
CONCLUSIONS: In conclusion, it can be stated that pyrimidinophanes are promising lead scaffold structures for further design of specific ligands for the PAS of AChE. Also AChE inhibitors with a 6-methyluracil moiety may be considered as potential drugs for the treatment of pathological muscle weakness syndromes.
ESTHER : Petrov_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S72
PubMedSearch : Petrov_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S72
PubMedID: 26639720

Title : 6-Methyluracil derivatives as acetylcholinesterase inhibitors for treatment of Alzheimer's disease - Zueva_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S69
Author(s) : Zueva IV , Semenov VE , Mukhamedyarov MA , Lushchekina SV , Kharlamova AD , Petukhova EO , Mikhailov AS , Podyachev SN , Saifina LF , Petrov KA , Minnekhanova OA , Zobov VV , Nikolsky EE , Masson P , Reznik VS
Ref : Int J Risk Saf Med , 27 Suppl 1 :S69 , 2015
Abstract : BACKGROUND: Alzheimer's disease (AD) is the major age-related progressive neurodegenerative disorder. The brain of AD patients suffers from loss of cholinergic neurons and decreased number of synapses [1]. AD is caused by an imbalance between Abeta production and clearance, resulting in increased amount of Abeta in various forms [2]. Reduction of Abeta production and increasing clearance of Abeta pathogenic forms are key targets in the development of potential therapeutic agents for AD treatment. Unfortunately, only nosotropic approaches for treatment of AD are currently effective in humans. These approaches mainly focus on the inhibition of brain acetyl-cholinesterase (AChE) to increase lifetime of cerebral acetylcholine [3]. It is important to emphasize that AChE itself promotes the formation of Abeta fibrils in vitro and Abeta plaques in the cerebral cortex of transgenic mouse models of AD [4]. This property of AChE results from interaction between Abeta and the peripheral anionic site of the enzyme (PAS) [5]. Dual binding site inhibitors of both catalytic active site (CAS) and PAS can simultaneously improve cognition and slow down the rate of Abeta-induced neural degeneration. Unfortunately, the assortment of AChE PAS ligands is still extremely limited. OBJECTIVE: To study putative advantages of AChE non-charged PAS inhibitors based on 6-methyluracil derivatives for the treatment of Alzheimer's disease.
METHODS: In vitro studies. Concentration of drug producing 50% of AChE/BuChE activity inhibition (IC50) was measured using the method of Ellman et al. [6]. Toxicological experiments were performed using IP injection of the different compounds in mice. LD50, dose (in mg/kg) causing lethal effects in 50% of animals was taken as a criterion of toxicity [7]. The ability of compound to block in vitro AChE-induced Abeta1-40 aggregation was studied using a thioflavin T (ThT) fluorescent probe [8].In vivo biological assays. For in vivo blood-brain barrier permeation assay brains were removed 30 min after IP injection of LD50 dose of tested compound injection. The inhibitory potency was measured using the method of Ellman.Scopolamine and transgenic models of AD were used to evaluate the influence of compound 35 on spatial memory performance.Water solution of scopolamine was injected to mice (ip) 20 minutes before starting memory test during 14 days [9]. Mice were assigned to 7 groups, including 4 groups receiving injection (ip) of compound in different dosages, donepezil-treated mice (donepezil is conventionally used to treat Alzheimer's disease), positive and negative control groups. Double transgenic (APP/PS1) mice expressing a chimeric mouse/human amyloid precursor protein and a mutant of human presenilin-1 [10] were assigned to 4 groups, including transgenic animals injected (ip) with compound 35 or donepezil solution, positive (transgenes injected with water) and negative (wild-type mice) controls.To evaluate spatial memory performance, mice were trained on a reward alternation task using a conventional T-maze [11]. The criterion for a mouse having learned the rewarded alternation task was 3 consecutive days of at least 5 correct responses out of the 6 free trials.For beta-amyloid peptide load was evaluated quantitatively as a number and summary area of Thioflavine S fluorescent spots in cerebral cortex and hippocampal images using Image J program. Statistical analyses were performed using the Mann-Whitney test.
RESULTS: We evaluated the acute toxicity of the most active compounds. The most potent AChE inhibitor compound 35 (IC50 (AChE) = 5 +/- 0.5 nM) exhibited the lowest LD50 values (51 mg/kg) and inhibited brain AChE by more than 71 +/- 1%. Compound 35 at 10 nM, exhibited a significant (35 +/- 9%) inhibitory activity toward human AChE-induced Abeta aggregation.Scopolamine injection induced significant decrease in correct choice percentage in T-maze, as well as decrease in percentage of mice reaching criterion for learning the task by day 14. This memory deficit was relieved to some extent either by compound 35 (5 mg/kg) or donepezil (reference compound) treatment (0.75 mg/kg). Interestingly, higher doses of compound 35 (10 and 15 mg/kg) produced less therapeutic effect on spatial memory deficit.Group of APP/PS1 mice showed 3 times lower percentage of reaching behavioral criterion and lower percentage of correct choice in T-maze alternation task comparing to WT mice, whereas compound 35 (5 mg/kg) or Donepezil treatment effectively improved these parameters in APP/PS1 mice.Compound 35 treatment (5 mg/kg) during 14 days significantly reduced percentage of summary area and number of beta-amyloid peptide (betaAP) deposits visualized in sections of cerebral cortex, dentate gyrus, and hippocampal CA3 area in APP/PS1 mice. The most prominent reduction of betaAP load by compound 35 treatment was found in CA3 area and cerebral cortex. Meanwhile, Donepezil treatment (1 mg/kg) during 14 days significantly reduced betaAP load in cerebral cortex but not in dentate gyrus and CA3 area.
CONCLUSIONS: Experiments showed that the most potent AChE inhibitor compound 35 (6-methyluracil derivative) permeated the blood-brain barrier, improved working memory in the APP/PS1 transgenic mice and significantly reduced the number and area of Abeta plaques in the brain. Thus, compound 35 is a promising candidate as a bi-functional inhibitor of AChE for treatment of AD.
ESTHER : Zueva_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S69
PubMedSearch : Zueva_2015_Int.J.Risk.Saf.Med_27 Suppl 1_S69
PubMedID: 26639718

Title : Luminescent silica nanoparticles for sensing acetylcholinesterase-catalyzed hydrolysis of acetylcholine - Mukhametshina_2015_Biosens.Bioelectron_77_871
Author(s) : Mukhametshina AR , Fedorenko SV , Zueva IV , Petrov KA , Masson P , Nizameev IR , Mustafina AR , Sinyashin OG
Ref : Biosensors & Bioelectronics , 77 :871 , 2015
Abstract : This work highlights the H-function of Tb(III)-doped silica nanoparticles in aqueous solutions of acetic acid as a route to sense acetylcholinesterase-catalyzed hydrolysis of acetylcholine (ACh). The H-function results from H+-induced quenching of Tb(III)-centered luminescence due to protonation of Tb(III) complexes located close to silica/water interface. The H-function can be turned on/switched off by the concentration of complexes within core or nanoparticle shell zones, by the silica surface decoration and adsorption of both organic and inorganic cations on silica surface. Results indicate the optimal synthetic procedure for making nanoparticles capable of sensing acetic acid produced by enzymatic hydrolysis of acetylcholine. The H-function of nanoparticles was determined at various concentrations of ACh and AChE. The measurements show experimental conditions for fitting the H-function to Michaelis-Menten kinetics. Results confirm that reliable fluorescent monitoring AChE-catalyzed hydrolysis of ACh is possible through the H-function properties of Tb(III)-doped silica nanoparticles.
ESTHER : Mukhametshina_2015_Biosens.Bioelectron_77_871
PubMedSearch : Mukhametshina_2015_Biosens.Bioelectron_77_871
PubMedID: 26516688

Title : 6-Methyluracil Derivatives as Bifunctional Acetylcholinesterase Inhibitors for the Treatment of Alzheimer's Disease - Semenov_2015_ChemMedChem_10_1863
Author(s) : Semenov VE , Zueva IV , Mukhamedyarov MA , Lushchekina SV , Kharlamova AD , Petukhova EO , Mikhailov AS , Podyachev SN , Saifina LF , Petrov KA , Minnekhanova OA , Zobov VV , Nikolsky EE , Masson P , Reznik VS
Ref : ChemMedChem , 10 :1863 , 2015
Abstract : Novel 6-methyluracil derivatives with omega-(substituted benzylethylamino)alkyl chains at the nitrogen atoms of the pyrimidine ring were designed and synthesized. The numbers of methylene groups in the alkyl chains were varied along with the electron-withdrawing substituents on the benzyl rings. The compounds are mixed-type reversible inhibitors of cholinesterases, and some of them show remarkable selectivity for human acetylcholinesterase (hAChE), with inhibitory potency in the nanomolar range, more than 10 000-fold higher than that for human butyrylcholinesterase (hBuChE). Molecular modeling studies indicate that these compounds are bifunctional AChE inhibitors, spanning the enzyme active site gorge and binding to its peripheral anionic site (PAS). In vivo experiments show that the 6-methyluracil derivatives are able to penetrate the blood-brain barrier (BBB), inhibiting brain-tissue AChE. The most potent AChE inhibitor, 3 d (1,3-bis[5-(o-nitrobenzylethylamino)pentyl]-6-methyluracil), was found to improve working memory in scopolamine and transgenic APP/PS1 murine models of Alzheimer's disease, and to significantly decrease the number and area of beta-amyloid peptide plaques in the brain.
ESTHER : Semenov_2015_ChemMedChem_10_1863
PubMedSearch : Semenov_2015_ChemMedChem_10_1863
PubMedID: 26412714

Title : Schwann Cells Sense and Control Acetylcholine Spillover at the Neuromuscular Junction by alpha7 Nicotinic Receptors and Butyrylcholinesterase - Petrov_2014_J.Neurosci_34_11870
Author(s) : Petrov KA , Girard E , Nikitashina AD , Colasante C , Bernard V , Nurullin LF , Leroy J , Samigullin D , Colak O , Nikolsky EE , Plaud B , Krejci E
Ref : Journal of Neuroscience , 34 :11870 , 2014
Abstract : Terminal Schwann cells (TSCs) are key components of the mammalian neuromuscular junction (NMJ). How the TSCs sense the synaptic activity in physiological conditions remains unclear. We have taken advantage of the distinct localization of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) at the NMJ to bring out the function of different ACh receptors (AChRs). AChE is clustered by the collagen Q in the synaptic cleft and prevents the repetitive activation of muscle nicotinic AChRs. We found that BChE is anchored at the TSC by a proline-rich membrane anchor, the small transmembrane protein anchor of brain AChE. When BChE was specifically inhibited, ACh release was significant depressed through the activation of alpha7 nAChRs localized on the TSC and activated by the spillover of ACh. When both AChE and BChE were inhibited, the spillover increased and induced a dramatic reduction of ACh release that compromised the muscle twitch triggered by the nerve stimulation. alpha7 nAChRs at the TSC may act as a sensor for spillover of ACh adjusted by BChE and may represent an extrasynaptic sensor for homeostasis at the NMJ. In myasthenic rats, selective inhibition of AChE is more effective in rescuing muscle function than the simultaneous inhibition of AChE and BChE because the concomitant inhibition of BChE counteracts the positive action of AChE inhibition. These results show that inhibition of BChE should be avoided during the treatment of myasthenia and the pharmacological reversal of residual curarization after anesthesia.
ESTHER : Petrov_2014_J.Neurosci_34_11870
PubMedSearch : Petrov_2014_J.Neurosci_34_11870
PubMedID: 25186736

Title : Regulation of acetylcholinesterase activity by nitric oxide in rat neuromuscular junction via N-methyl-d-aspartate receptor activation - Petrov_2013_Eur.J.Neurosci_37_181
Author(s) : Petrov KA , Malomouzh AI , Kovyazina IV , Krejci E , Nikitashina AD , Proskurina SE , Zobov VV , Nikolsky EE
Ref : European Journal of Neuroscience , 37 :181 , 2013
Abstract : Acetylcholinesterase (AChE) is an enzyme that hydrolyses the neurotransmitter acetylcholine, thereby limiting spillover and duration of action. This study demonstrates the existence of an endogenous mechanism for the regulation of synaptic AChE activity. At the rat extensor digitorum longus neuromuscular junction, activation of N-methyl-d-aspartate (NMDA) receptors by combined application of glutamate and glycine led to enhancement of nitric oxide (NO) production, resulting in partial AChE inhibition. Partial AChE inhibition was measured using increases in miniature endplate current amplitude. AChE inhibition by paraoxon, inactivation of NO synthase by N(omega) -nitro-l-arginine methyl ester, and NMDA receptor blockade by dl-2-amino-5-phosphopentanoic acid prevented the increase in miniature endplate current amplitude caused by amino acids. High-frequency (10 Hz) motor nerve stimulation in a glycine-containing bathing solution also resulted in an increase in the amplitude of miniature endplate currents recorded during the interstimulus intervals. Pretreatment with an NO synthase inhibitor and NMDA receptor blockade fully eliminated this effect. This suggests that endogenous glutamate, released into the synaptic cleft as a co-mediator of acetylcholine, is capable of triggering the NMDA receptor/NO synthase-mediated pathway that modulates synaptic AChE activity. Therefore, in addition to well-established modes of synaptic plasticity (e.g. changes in the effectiveness of neurotransmitter release and/or the sensitivity of the postsynaptic membrane), another mechanism exists based on the prompt regulation of AChE activity.
ESTHER : Petrov_2013_Eur.J.Neurosci_37_181
PubMedSearch : Petrov_2013_Eur.J.Neurosci_37_181
PubMedID: 23121214

Title : Specific inhibitory effects of the alkylammonium derivative 6-methyluracil on acetylcholinesterase of smooth and striated muscles in rats -
Author(s) : Nikitashina AD , Petrov KA , Zobov VV , Reznik VS , Nikolsky EE
Ref : Dokl Biol Sci , 449 :82 , 2013
PubMedID: 23652433

Title : Effect of tissue-specific acetylcholinesterase inhibitor C-547 on alpha3beta4 and alphabetaepsilondelta acetylcholine receptors in COS cells - Lindovsky_2012_Eur.J.Pharmacol_688_22
Author(s) : Lindovsky J , Petrov KA , Krusek J , Reznik VS , Nikolsky EE , Vyskocil F
Ref : European Journal of Pharmacology , 688 :22 , 2012
Abstract : The C-547 is the most effective muscle and tissue-specific anticholinesterase among alkylammonium derivatives of 6-methyluracil (ADEMS) acting in nanomolar concentrations on locomotor muscles but not on respiratory muscles, smooth muscles and heart and brain acetylcholine esterases (AChE). When applied systematically it could influence peripheral acetylcholine receptors. The aim of the present study was to investigate the effect of C-547 on rat alpha3beta4 (ganglionic type) and alphabetaepsilondelta (muscle type) nicotinic receptors expressed in COS cells. Currents evoked by rapid application of acetylcholine or nicotine were recorded in whole-cell mode by electrophysiological patch-clamp technique 2-4 days after cell transfection by plasmids coding the alpha3beta4 or alphabetaepsilondelta combination of receptor subunits. In cells sensitive to acetylcholine, the application of C-547 evoked no responses. When acetylcholine was applied during an already running application of C-547, acetylcholine responses were only inhibited at concentrations higher than 10(-7)M. This inhibition is not voltage-dependent, but is accompanied by an increased rate of desensitization. Thus in both types of receptors, effective doses are approximately 100 times higher than those inhibiting AChE in leg muscles and similar to those inhibiting respiratory diaphragm muscles and external intercostal muscles. These observations show that C-547 can be considered for symptomatic treatment of myasthenia gravis and other congenital myasthenic syndromes as an inhibitor of AChE in leg muscles at concentrations much lower than those inhibiting muscle and ganglion types of acetylcholine receptors.
ESTHER : Lindovsky_2012_Eur.J.Pharmacol_688_22
PubMedSearch : Lindovsky_2012_Eur.J.Pharmacol_688_22
PubMedID: 22634638

Title : Different sensitivities of rat skeletal muscles and brain to novel anti-cholinesterase agents, alkylammonium derivatives of 6-methyluracil (ADEMS) - Petrov_2011_Br.J.Pharmacol_163_732
Author(s) : Petrov KA , Yagodina LO , Valeeva GR , Lannik NI , Nikitashina AD , Rizvanov AA , Zobov VV , Bukharaeva EA , Reznik VS , Nikolsky EE , Vyskocil F
Ref : British Journal of Pharmacology , 163 :732 , 2011
Abstract : BACKGROUND AND PURPOSE: The rat respiratory muscle diaphragm has markedly lower sensitivity than the locomotor muscle extensor digitorum longus (EDL) to the new acetylcholinesterase (AChE) inhibitors, alkylammonium derivatives of 6-methyluracil (ADEMS). This study evaluated several possible reasons for differing sensitivity between the diaphragm and limb muscles and between the muscles and the brain. EXPERIMENTAL APPROACH: Increased amplitude and prolonged decay time of miniature endplate currents were used to assess anti-cholinesterase activity in muscles. In hippocampal slices, induction of synchronous network activity was used to follow cholinesterase inhibition. The inhibitor sensitivities of purified AChE from the EDL and brain were also estimated. KEY RESULTS: The intermuscular difference in sensitivity to ADEMS is partly explained caused by a higher level of mRNA and activity of 1,3-bis[5(diethyl-o-nitrobenzylammonium)pentyl]-6-methyluracildibromide (C-547)-resistant BuChE in the diaphragm. Moreover, diaphragm AChE was more than 20 times less sensitive to C-547 than that from the EDL. Sensitivity of the EDL to C-547 dramatically decreased after treadmill exercises that increased the amount of PRiMA AChE(G4), but not ColQ AChE(A12) molecular forms. The A12 form present in muscles appeared more sensitive to C-547. The main form of AChE in brain, PRiMA AChE(G4), was apparently less sensitive because brain cholinesterase activity was almost three orders of magnitude more resistant to C-547 than that of the EDL. CONCLUSIONS AND IMPLICATIONS: Our findings suggest that ADEMS compounds could be used for the selective inhibition of AChEs and as potential therapeutic tools.
ESTHER : Petrov_2011_Br.J.Pharmacol_163_732
PubMedSearch : Petrov_2011_Br.J.Pharmacol_163_732
PubMedID: 21232040

Title : [The study of effects of a novel acetylcholinesterase inhibitor on electrical activity of the heart] - Abramochkin_2009_Kardiologiia_49_47
Author(s) : Abramochkin DV , Petrov KA , Zobov VV , Iagodina LO , Nikol'skii EE , Rozenshtraukh LV
Ref : Kardiologiia , 49 :47 , 2009
Abstract : We have investigated effect of a representative of the novel class of selective acetylcholinesterase inhibitors A 1,3-bis[5(diethyl-o-nitrobenzyl ammonio) penthyl]-6-methyluracildibromide (compound 547) on duration and rhythm of sequence of right atrial action potential (AP) as well as on kinetics of acetylcholinesterase catalyzed reaction in homogenates of skeletal muscle (m. extensor digitorum longus) and cardiac muscle in the rat. We have shown that contrary to classical acetylcholinesterase inhibitors armin and proserin none of studied concentrations (1, 10 and 100 nM) of compound 547 exerted significant effect on AP configuration and rate of sinus rhythm. Compound 547 belongs to noncompetitive type with K1(heart)=3.6 x 10(-4) M and K1(EDL)=1.3 x 10(-8) M. Proserin exerts comparable inhibitory action on reaction in the heart and skeletal muscle, its K1(heart)=0.73 x 10(-5) M and K1(EDL) = 0.4 x 10(-5) M. Thus low sensitivity of myocardium to compound 547 in electrophysiological experiments is not related to lesser availability of synaptic acetylcholinesterase in the heart compared with acetylcholinesterase in skeletal muscles but reaction catalyzed by cardiac acetylcholinesterase is actually to a substantial degree less prone to inhibition by compound 547.
ESTHER : Abramochkin_2009_Kardiologiia_49_47
PubMedSearch : Abramochkin_2009_Kardiologiia_49_47
PubMedID: 19166401

Title : Mechanisms of cardiac muscle insensitivity to a novel acetylcholinesterase inhibitor C-547 - Abramochkin_2009_J.Cardiovasc.Pharmacol_53_162
Author(s) : Abramochkin DV , Petrov KA , Zobov VV , Yagodina LO , Nikolsky EE , Rosenshtraukh LV
Ref : J Cardiovasc Pharmacol , 53 :162 , 2009
Abstract : We compared the effects of the novel acetylcholinesterase (AChE) inhibitor C-547 on action potential configuration and sinus rhythm in the isolated right atrium preparation of rat with those of armin and neostigmine. Both armin (10(-7), 10(-6), and 10(-5) M) and neostigmine (10(-7), 10(-6), and 5 x 10(-6) M) produced a marked decrease in action potential duration and slowing of sinus rate. These effects were abolished by atropine and are attributable to the accumulation of acetylcholine in the myocardium. The novel selective AChE inhibitor C-547 (10(-9) to 10(-7) M), an alkylammonium derivative of 6-methyluracil, had no such effects. The inhibition constant of C-547 on cardiac AChE is 40-fold higher than that on extensor digitorum longus muscle AChE. These results suggest that C-547 might be employed to treat diseases such as myasthenia gravis or Alzheimer disease, without having unwanted effects on the heart.
ESTHER : Abramochkin_2009_J.Cardiovasc.Pharmacol_53_162
PubMedSearch : Abramochkin_2009_J.Cardiovasc.Pharmacol_53_162
PubMedID: 19188831

Title : Different sensitivity of miniature endplate currents in rat external and internal intercostal muscles to the acetylcholinesterase inhibitor C-547 as compared with diaphragm and extensor digitorum longus - Petrov_2009_Physiol.Res_58_149
Author(s) : Petrov KA , Kovyazina IV , Zobov VV , Bukharaeva EA , Nikolsky EE , Vyskocil F
Ref : Physiol Res , 58 :149 , 2009
Abstract : Derivative of 6-methyluracil, selective cholinesterase inhibitor C-547 potentiates miniature endplate currents (MEPCs) in rat external intercostal muscles (external ICM) more effectively than in internal intercostal muscles (internal ICM). Effect of the C-547 on intercostal muscles was compared with those on extensor digitorum longus (EDL) and diaphragm muscles. Half-effective concentrations for tau of MEPC decay arranged in increasing order were as follows: EDL, locomotor muscle, most sensitive = 1.3 nM, external ICM, inspiration muscle = 6.8 nM, diaphragm, main inspiration muscle = 28 nM, internal ICM, expiration muscle = 71 nM. External ICM might therefore be inhibited, similarly as the limb muscles, by nanomolar concentrations of the drug and do not participate in inspiration in the presence of the C-547. Moreover, internal ICM inhibition can hinder the expiration during exercise-induced fast breathing of C-547- treated experimental animals.
ESTHER : Petrov_2009_Physiol.Res_58_149
PubMedSearch : Petrov_2009_Physiol.Res_58_149
PubMedID: 19331513

Title : Effect of a tetraalkylammonium derivative of 6-methyluracil from a new class of acetylcholinesterase inhibitors on the endplate potential amplitude in muscles of different function types under high-frequency nerve stimulation -
Author(s) : Petrov KA , Kovyazina IV , Zobov VV , Bukharaeva EA , Reznik VS , Nikolsky EE
Ref : Dokl Biol Sci , 415 :261 , 2007
PubMedID: 17929660

Title : Different sensitivity of miniature endplate currents of the rat extensor digitorum longus, soleus and diaphragm muscles to a novel acetylcholinesterase inhibitor C-547 - Petrov_2006_Physiol.Res_55_585
Author(s) : Petrov KA , Kovyazina LV , Zobov VV , Bukharaeva EA , Nikolsky EE , Vyskocil F
Ref : Physiol Res , 55 :585 , 2006
Abstract : A novel derivative of 6-methyluracil, C-547, increased the amplitude and prolonged the duration of miniature endplate currents (MEPCs) which is typical for acetylcholinesterase inhibition. In the soleus and extensor digitorum longus significant potentiation was detected at nanomolar concentrations. In contrast, in the diaphragm muscle, the increase in the amplitudes of the MEPCs and the decay time constant appeared only when the concentration of C-547 was elevated to 1 x 10(-7) M. Possible consequences for the exploitation of this drug, which can selectively inhibit AChE in particular synapses, are discussed.
ESTHER : Petrov_2006_Physiol.Res_55_585
PubMedSearch : Petrov_2006_Physiol.Res_55_585
PubMedID: 16792471

Title : Selective blockade of locomotor muscles by uracil-containing tetraalkylammonium acetylcholinesterase inhibitors -
Author(s) : Zobov VV , Petrov KA , Asliamova AA , Beresinskii LA , Akamsin VD , Galiametdinova IV , Reznik VS
Ref : Dokl Biol Sci , 401 :77 , 2005
PubMedID: 16003862