pseudo-irreversible inhibition
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In this review, the current progress in the research and development of butyrylcholinesterase (BChE) reactivators is summarised and the advantages or disadvantages of these reactivators are critically discussed. Organophosphorus compounds such as nerve agents (sarin, tabun, VX) or pesticides (chlorpyrifos, diazinon) cause irreversible inhibition of acetylcholinesterase (AChE) and BChE in the human body. While AChE inhibition can be life threatening due to cholinergic overstimulation and crisis, selective BChE inhibition has presumably no adverse effects. Because BChE is mostly found in plasma, its activity is important for the scavenging of organophosphates before they can reach AChE in the central nervous system. Therefore, this enzyme in combination with its reactivator can be used as a pseudo-catalytic scavenger of organophosphates. Three structural types of BChE reactivators were found, i.e. bisquaternary salts, monoquaternary salts and uncharged compounds. Although the reviewed reactivators have certain limitations, the promising candidates for BChE reactivation were found in each structural group.
- MeSH
- acetylcholinesterasa metabolismus chemie MeSH
- butyrylcholinesterasa * metabolismus chemie MeSH
- cholinesterasové inhibitory * chemie farmakologie chemická syntéza MeSH
- lidé MeSH
- molekulární struktura MeSH
- organofosforové sloučeniny * chemie farmakologie MeSH
- reaktivátory cholinesterasy farmakologie chemie chemická syntéza MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
The development of novel inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) represents a viable approach to alleviate Alzheimer's disease. Thirty-six halogenated 2-hydroxy-N-phenylbenzamides (salicylanilides) with various substitution patterns and their esters with phosphorus-based acids were synthesized in yields of 72% to 92% and characterized. They were evaluated for in vitro inhibition of AChE from electric eel and BuChE from equine serum using modified Ellman's spectrophotometric method. The benzamides exhibited a moderate inhibition of AChE with IC50 values in a narrow concentration range from 33.1 to 85.8 µM. IC50 values for BuChE were higher (53.5-228.4 µM). The majority of derivatives inhibit AChE more efficiently than BuChE and are comparable or superior to rivastigmine-an established cholinesterases inhibitor used in the treatment of Alzheimer's disease. Phosphorus-based esters especially improved the activity against BuChE with 5-chloro-2-{[4-(trifluoromethyl)phenyl]carbamoyl}phenyl diethyl phosphite 5c superiority (IC50 = 2.4 µM). This derivative was also the most selective inhibitor of BuChE. It caused a mixed inhibition of both cholinesterases and acted as a pseudo-irreversible inhibitor. Several structure-activity relationships were identified, e.g., favouring esters and benzamides obtained from 5-halogenosalicylic acids and polyhalogenated anilines. Both 2-hydroxy-N-phenylbenzamides and esters share convenient physicochemical properties for blood-brain-barrier penetration and thus central nervous system delivery.
- MeSH
- acetylcholinesterasa metabolismus MeSH
- benzamidy chemie farmakologie MeSH
- butyrylcholinesterasa metabolismus MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- Electrophorus MeSH
- estery chemie farmakologie MeSH
- fosfor chemie MeSH
- inhibiční koncentrace 50 MeSH
- koně MeSH
- molekulární struktura MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Rivastigmin je centrální inhibitor cholinesteráz (acetyl- i butyrylcholinesterázy). Vlastním mechanismem účinku je tzv. pseudoireverzibilní inhibice cholinesteráz. Dojde tak k zablokování enzymu odbourávajících acetylcholin a ke zvýšení počtu molekul tohoto neuromediátoru. Rivastigmin účinkuje selektivně v hippocampu a neokortexu, tedy oblastech mozku, které jsou při Alzheimerově demenci nejvíce postiženy. Tato vlastnost vyplývá z přednostní inhibice G1 izoformy acetylcholinesterázy. Nežádoucím účinkem jsou nejčastěji gastrointestinální obtíže, předejít jim lze pomocí titrace dávky. Rivastigmin má nízký potenciál pro vznik lékových interakcí.
Rivastigmine is a central inhibitor of cholinesterases (acetyl- and butyrylcholinesterases). Its mode of action is the so-called pseudo-irreversible inhibition of cholinesterases. This results in a blockage of enzymes which breakdown acetylcholine and subsequently in the increase of the number of molecules of this neurotransmitter. Rivastigmine acts selectively in hippocampus and neocortex, i.e.in the areas of brain which are most severely affected by Alzheimer’s disease. This issues from the priority inhibition of G1 iso-form of acetylcholinesterase. Gastrointestinal complaints are the most frequent adverse effects which, however, may be avoided by a careful titration of the treatment dose. Rivastigmine shows a low potential for drug interactions.
- Klíčová slova
- EXELON,
- MeSH
- acetylcholinesterasa farmakokinetika farmakologie MeSH
- Alzheimerova nemoc etiologie farmakoterapie MeSH
- cholinesterasové inhibitory aplikace a dávkování farmakologie chemie MeSH
- demence s Lewyho tělísky etiologie farmakoterapie MeSH
- lékové interakce MeSH
- registrace MeSH
- Publikační typ
- přehledy MeSH
The present experiment was aimed at assessing the application of neostigmine, an acetylcholinesterase (AChE) pseudo-irreversible inhibitor with poor penetration through the hematoencephalitic barrier, and the neurotransmitter acetylcholine (ACh). The experiment was done to evaluate their ability to modulate an infectious disease: tularemia. Mice infected with Franciselle tularensis and exposed to either ACh or neostigmine had a higher mortality and spleen bacterial burden when compared to infected mice exposed to saline solution only. The activated cholinergic anti-inflammatory pathway suppressed pathways necessary for tularemia resolution. Administration of AChE inhibitors to the individuals suffering from tularemia is contra-indicatory. Drugs based on AChE inhibition should be restricted when tularemia or disease with a similar pathogenesis is suspected.
- MeSH
- acetylcholin * imunologie toxicita MeSH
- cytokiny účinky léků MeSH
- Francisella tularensis patogenita MeSH
- imunomodulace MeSH
- myši inbrední BALB C MeSH
- neostigmin * imunologie toxicita MeSH
- parasympatický nervový systém účinky léků MeSH
- tularemie * imunologie komplikace mortalita MeSH
- výzkum MeSH
- zánět imunologie mikrobiologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Based on the presence of dialkyl phosphate moiety, we evaluated twenty-seven salicylanilide diethyl phosphates (diethyl [2-(phenylcarbamoyl)phenyl] phosphates) for the inhibition of acetylcholinesterase (AChE) from electric eel (Electrophorus electricus L.) and butyrylcholinesterase (BChE) from equine serum. Ellman's spectrophotometric method was used. The inhibitory activity (expressed as IC50 values) was compared with that of the established drugs galantamine and rivastigmine. Salicylanilide diethyl phosphates showed significant activity against both cholinesterases with IC50 values from 0.903 to 86.3 μM. IC50s for BChE were comparatively lower than those obtained for AChE. All of the investigated compounds showed higher inhibition of AChE than rivastigmine, and six of them inhibited BChE more effectively than both rivastigmine and galantamine. In general, derivatives of 4-chlorosalicylic acid showed enhanced activity when compared to derivatives of 5-halogenated salicylic acids, especially against BChE. The most effective inhibitor of AChE was O-{5-chloro-2-[(3-bromophenyl)carbamoyl]phenyl} O,O-diethyl phosphate with IC50 of 35.4 μM, which is also one of the most potent inhibitors of BChE. O-{5-Chloro-2-[(3,4-dichlorophenyl)carbamoyl]phenyl} O,O-diethyl phosphate exhibited in vitro the strongest inhibition of BChE (0.90 μM). Salicylanilide diethyl phosphates act as pseudo-irreversible cholinesterases inhibitors.
To date, the only treatments developed for poisoning by organophosphorus compounds, the most toxic chemical weapons of mass destruction, have exhibited limited efficacy and versatility. The available causal antidotes are based on reactivation of the enzyme acetylcholinesterase (AChE), which is rapidly and pseudo-irreversibly inhibited by these agents. In this study, we developed a novel series of monoquaternary reactivators combining permanently charged moieties tethered to position 6- of 3-hydroxypyridine-2-aldoxime reactivating subunit. Highlighted representatives (21, 24, and 27; also coded as K1371, K1374, and K1375, respectively) that contained 1-phenylisoquinolinium, 7-amino-1-phenylisoquinolinium and 4-carbamoylpyridinium moieties as peripheral anionic site ligands, respectively, showed efficacy superior or comparable to that of the clinically used standards. More importantly, these reactivators exhibited wide-spectrum efficacy and were minutely investigated via determination of their reactivation kinetics in parallel with molecular dynamics simulations to study their mechanisms of reactivation of the tabun-inhibited AChE conjugate. To further confirm the potential applicability of these candidates, a mouse in vivo assay was conducted. While K1375 had the lowest acute toxicity and the most suitable pharmacokinetic profile, the oxime K1374 with delayed elimination half-life was the most effective in ameliorating the signs of tabun toxicity. Moreover, both in vitro and in vivo, the versatility of the agents was substantially superior to that of clinically used standards. Their high efficacy and broad-spectrum capability make K1374 and K1375 promising candidates that should be further investigated for their potential as nerve agents and insecticide antidotes.
- MeSH
- acetylcholinesterasa účinky léků metabolismus MeSH
- antidota chemická syntéza chemie farmakologie MeSH
- myši inbrední BALB C MeSH
- myši MeSH
- oximy chemická syntéza chemie farmakologie MeSH
- reaktivátory cholinesterasy chemická syntéza chemie farmakologie MeSH
- simulace molekulární dynamiky MeSH
- vztahy mezi strukturou a aktivitou MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
