C-547, a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase: Pharmacokinetic and pharmacodynamic studies

Петров, К. А.; Zueva, Irina V.; Kovyazina, I. V.; Sedov, Igor A.; Lushchekina, Sofya V.; Kharlamova, Alexandra D.; Lenina, Oksana A.; Кошкин, С. А.; Shtyrlin, Yu. G.; Nikolsky, E. E.; Masson, Patrick

doi:10.1016/j.neuropharm.2017.12.034

Cited by 12 publications

(11 citation statements)

References 39 publications

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“…At the moment, only the carbamylating agent pyridostigmine bromide is used as ChEs inhibitor for treatment of muscle weakness symptoms. However, the selectivity of pyridostigmine for AChE versus BChE is low (6 against >10,000 for C-547; Petrov et al, 2018b ). Taking into account ACh release down regulation under conditions of BChE inhibition, we can also conclude that selective inhibitors of AChE vs. BChE may have an advantage for MG treatment over non-selective ChE inhibitors, like pyridostigmine.…”

Section: Discussionmentioning

confidence: 99%

“…Very few slow-binding inhibitors of AChE have been used for their pharmacological properties and they have not been analyzed in terms of micro-PK/PD mechanisms. However, a recent PK/PD study of a potent and highly selective inhibitor of AChE, C-547 ( Kharlamova et al, 2016 ), revealed micro-pharmacodynamic mechanisms taking place in NMJ ( Petrov et al, 2018b ).…”

Section: Nmj and Opportunity To Use Micro-pharmacodynamic Mechanismsmentioning

confidence: 99%

“…Thus, in confined anatomical space such as NMJ where there is a high density of AChE subunits, binding kinetics of C-547 to AChE is characterized by long residence time on target (τ = 20 min) ( Kharlamova et al, 2016 ) and slow diffusion rate of C-547 out of NMJ ( Petrov et al, 2018b ). This makes possible re-binding of C-547 to AChE, and therefore slow elimination from NMJ.…”

Section: Nmj and Opportunity To Use Micro-pharmacodynamic Mechanismsmentioning

confidence: 99%

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Autoregulation of Acetylcholine Release and Micro-Pharmacodynamic Mechanisms at Neuromuscular Junction: Selective Acetylcholinesterase Inhibitors for Therapy of Myasthenic Syndromes

2018

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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.

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Section: Discussionmentioning

confidence: 99%

Section: Nmj and Opportunity To Use Micro-pharmacodynamic Mechanismsmentioning

confidence: 99%

Section: Nmj and Opportunity To Use Micro-pharmacodynamic Mechanismsmentioning

confidence: 99%

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Autoregulation of Acetylcholine Release and Micro-Pharmacodynamic Mechanisms at Neuromuscular Junction: Selective Acetylcholinesterase Inhibitors for Therapy of Myasthenic Syndromes

2018

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“…As a consequence, ligand-binding kinetics controls the duration of drug action in micro-anatomical compartments. Therefore, potent slow-binding ligands with slow rate of dissociation from targets, re-binding and slow exit rate from micro-anatomical compartments, such as NMJ, display long-lasting action 23 .…”

mentioning

confidence: 99%

“…Concepts and methodology for analysis of micro PK/PD mechanisms and drug discovery have been developed in the past decade [23][24][25][26][27][28][29][30][31][32][33] . However, at the moment, very few slow-binding inhibitors of AChE have been used for their pharmacological properties and only one of them has been analyzed in terms of a micro PK/PD mechanism 23,34 .…”

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confidence: 99%

Slow-binding reversible inhibitor of acetylcholinesterase with long-lasting action for prophylaxis of organophosphate poisoning

Lenina

Zueva

Зобов

et al. 2020

Sci Rep

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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 2xLD50 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.

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α-tocopherol, a slow-binding inhibitor of acetylcholinesterase

Zueva

Lushchekina

Shulnikova

et al. 2021

Chemico-Biological Interactions

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C-547, a 6-methyluracil derivative with long-lasting binding and rebinding on acetylcholinesterase: Pharmacokinetic and pharmacodynamic studies

Cited by 12 publications

References 39 publications

Autoregulation of Acetylcholine Release and Micro-Pharmacodynamic Mechanisms at Neuromuscular Junction: Selective Acetylcholinesterase Inhibitors for Therapy of Myasthenic Syndromes

Autoregulation of Acetylcholine Release and Micro-Pharmacodynamic Mechanisms at Neuromuscular Junction: Selective Acetylcholinesterase Inhibitors for Therapy of Myasthenic Syndromes

Slow-binding reversible inhibitor of acetylcholinesterase with long-lasting action for prophylaxis of organophosphate poisoning

α-tocopherol, a slow-binding inhibitor of acetylcholinesterase

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