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  • 1
    Language: English
    In: Pharmacology and Therapeutics, August 2013, Vol.139(2), pp.249-259
    Description: Poisoning by organophosphorus compounds (OP) still is a major therapeutic problem. Intentional OP pesticide poisoning results in up to 300.000 deaths each year and highly toxic OP nerve agents pose a permanent threat for the civilian population and military forces. The therapeutic value of clinically used oximes, pralidoxime, obidoxime and TMB-4, in human OP pesticide poisoning is under debate. Moreover, these oximes lack efficacy in poisoning by various nerve agents. An innumerable number of novel oximes have been synthesized in the past five decades to provide more effective oximes and compounds with improved blood–brain-barrier penetration. Novel compounds were tested with largely different experimental protocols in vitro and in animals in vivo. The lack of comparable experimental conditions and the absence of human in vivo studies hamper a well-founded evaluation of the available data. At present, it appears that only a small number of (bispyridinium) oximes show superior potency and efficacy against individual OP. However, until now, no oxime with sufficient broad-spectrum activity against structurally different OP pesticides and nerve agents is available. An interim solution may be the combination of two oximes with overlapping reactivation spectrum. In conclusion, the unsatisfying situation calls for studies with standardized and comparable experimental conditions in order to allow a sound assessment of available and novel oximes.
    Keywords: Organophosphorus Compounds ; Pesticides ; Nerve Agents ; Oximes ; Acetylcholinesterase ; Therapy ; Pharmacy, Therapeutics, & Pharmacology
    ISSN: 0163-7258
    E-ISSN: 1879-016X
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  • 2
    Language: English
    In: Chemico-Biological Interactions, 2011, Vol.194(2), pp.91-96
    Description: Estimated MINA and HI-6 concentrations to reactivate nerve agent-inhibited human acetylcholinesterase. ► We investigated the reactivation kinetics of MINA with OP-inhibited human AChE. ► MINA exhibited an outstanding low affinity but moderate to high reactivity to inhibited AChE. ► These kinetic data indicate that huge MINA concentrations are required for an effective reactivation. Treatment of poisoning by highly toxic organophosphorus compounds (OP) with atropine and an acetylcholinesterase (AChE) reactivator (oxime) is of limited effectiveness in case of different nerve agents and pesticides. One challenge is the reactivation of OP-inhibited brain AChE which shows inadequate success with charged pyridinium oximes. Recent studies with high doses of the tertiary oxime isonitrosoacetone (MINA) indicated a beneficial effect on central and peripheral AChE and on survival in nerve agent poisoned guinea pigs. Now, an in vitro study was performed to determine the reactivation kinetics of MINA with tabun-, sarin-, cyclosarin-, VX- and paraoxon-inhibited human AChE. MINA showed an exceptionally low affinity to inhibited AChE but, with the exception of tabun-inhibited AChE, a moderate to high reactivity. In comparison to the pyridinium oximes obidoxime, 2-PAM and HI-6 the affinity and reactivity of MINA was in most cases lower and in relation to the most effective reactivators, the second order reactivation constant of MINA was 500 to 3400-fold lower. Hence, high in vivo MINA concentrations would be necessary to achieve at least partial reactivation. This assumption corresponds to in vivo data showing a dose-dependent effect on reactivation and survival in animals. In view, of the toxic potential of MINA in animals human studies would be necessary to determine the tolerability and pharmacokinetics of MINA in order to enable a proper assessment of the value of this oxime as an antidote in OP poisoning.
    Keywords: Isonitrosoacetone ; Organophosphorus Compounds ; Acetylcholinesterase ; Oximes ; Reactivation ; Kinetics ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0009-2797
    E-ISSN: 1872-7786
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  • 3
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 17 May 2016, Vol.113(20), pp.5514-9
    Description: Organophosphorus nerve agents interfere with cholinergic signaling by covalently binding to the active site of the enzyme acetylcholinesterase (AChE). This inhibition causes an accumulation of the neurotransmitter acetylcholine, potentially leading to overstimulation of the nervous system and death. Current treatments include the use of antidotes that promote the release of functional AChE by an unknown reactivation mechanism. We have used diffusion trap cryocrystallography and density functional theory (DFT) calculations to determine and analyze prereaction conformers of the nerve agent antidote HI-6 in complex with Mus musculus AChE covalently inhibited by the nerve agent sarin. These analyses reveal previously unknown conformations of the system and suggest that the cleavage of the covalent enzyme-sarin bond is preceded by a conformational change in the sarin adduct itself. Together with data from the reactivation kinetics, this alternate conformation suggests a key interaction between Glu202 and the O-isopropyl moiety of sarin. Moreover, solvent kinetic isotope effect experiments using deuterium oxide reveal that the reactivation mechanism features an isotope-sensitive step. These findings provide insights into the reactivation mechanism and provide a starting point for the development of improved antidotes. The work also illustrates how DFT calculations can guide the interpretation, analysis, and validation of crystallographic data for challenging reactive systems with complex conformational dynamics.
    Keywords: Acetylcholinesterase ; Crystallography ; Density Functional Theory ; Nerve Agent ; Reactivation ; Acetylcholinesterase -- Chemistry ; Antidotes -- Chemistry ; Cholinesterase Reactivators -- Chemistry ; Nerve Agents -- Chemistry ; Oximes -- Chemistry ; Pyridinium Compounds -- Chemistry ; Sarin -- Chemistry
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 4
    Language: English
    In: Toxicology Letters, 07 July 2012, Vol.212(1), pp.29-32
    Description: ► We investigated the kinetic interactions of a homologous series of oximes with native and cyclosarin-inhibited human AChE. ► The length of the oxime alkyl side chain was correlated with an increased affinity towards native AChE. ► The effect of the alkyl side chain on the affinity and reactivity towards phosphonylated AChE was moderate. ► In comparison to the reference oxime HI-6 all tested oximes had a lower reactivating potency. Inhibition of acetylcholinesterase (AChE) is the main toxic mechanism of organophosphorus compounds (OP) and reactivation of OP-inhibited AChE by oximes is a mainstay of antidotal treatment. The inadequate efficacy of clinically used oximes led to the synthesis of numerous new compounds in the past decades to identify more effective reactivators. Despite of extensive in vitro reactivation studies the structural features for the development of effective oximes are not well understood. In the present study we investigated the kinetic interactions of a homologous series of bispyridinium monoximes bearing C1 to C12 alkylketone groups on the second pyridinium ring with native and cyclosarin-inhibited human AChE. We observed a correlation of the length of the alkyl side chain with an up to 20-fold increased affinity towards native AChE. The effect of the alkyl side chain on the affinity and reactivity towards phosphonylated AChE was moderate, except of a markedly reduced reactivity of C10 and C12 oximes. In comparison to the reference oxime HI-6 all HGG oximes had a lower reactivating potency and these oximes are not considered as promising compounds for the reactivation of cyclosarin-inhibited AChE.
    Keywords: Acetylcholinesterase ; Organophosphorus Compound ; Oximes ; Reactivation ; Kinetics ; Structure–Activity Relationship ; Pharmacy, Therapeutics, & Pharmacology ; Public Health
    ISSN: 0378-4274
    E-ISSN: 1879-3169
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  • 5
    Language: English
    In: Toxicology Letters, 2011, Vol.200(1), pp.19-23
    Description: Previous in vitro studies showed marked species differences in the reactivating efficiency of oximes between human and animal acetylcholinesterase (AChE) inhibited by organophosphorus (OP) nerve agents. These findings provoked the present in vitro study which was designed to determine the inhibition, aging, spontaneous and oxime-induced reactivation kinetics of the pesticide paraoxon, serving as a model compound for diethyl-OP, and the oximes obidoxime, pralidoxime, HI 6 and MMB-4 with human, Rhesus monkey, swine, rabbit, rat and guinea pig erythrocyte AChE. Comparable results were obtained with human and monkey AChE. Differences between human, swine, rabbit, rat and guinea pig AChE were determined for the inhibition and reactivation kinetics. A six-fold difference of the inhibitory potency of paraoxon with human and guinea pig AChE was recorded while only moderate differences of the reactivation constants between human and animal AChE were determined. Obidoxime was by far the most effective reactivator with all tested species. Only minor species differences were found for the aging and spontaneous reactivation kinetics. The results of the present study underline the necessity to determine the inhibition, aging and reactivation kinetics in vitro as a basis for the development of meaningful therapeutic animal models, for the proper assessment of in vivo animal data and for the extrapolation of animal data to humans.
    Keywords: Organophosphorus Compound ; Paraoxon ; Acetylcholinesterase ; Oximes ; Kinetics ; Species Differences ; Pharmacy, Therapeutics, & Pharmacology ; Public Health
    ISSN: 0378-4274
    E-ISSN: 1879-3169
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  • 6
    Language: English
    In: Chemico-Biological Interactions, 25 March 2013, Vol.203(1), pp.125-128
    Description: ► We evaluated the kinetic interactions of a series of bispyridinium oximes with phosphylated human AChE. ► The position of the oxime group(s) is decisive for the reactivating potency. ► Different positions of oxime group(s) are important for different organophosphates. ► The nature of the linker, oxybismethylene or trimethylene, is obviously of minor importance. ► No single oxime was effective against structurally different organophosphorus inhibitors. Treatment of poisoning by various organophosphorus (OP) nerve agents with established acetylcholinesterase (AChE) reactivators (oximes) is insufficient. In consequence, extensive research programs have been undertaken in various countries in the past decades to identify more effective oximes. The efficacy of new compounds has been investigated with different in vitro and in vivo models which hamper the comparison of results from different laboratories. The crucial mechanism of action of oximes is the reactivation of phosphylated AChE. The kinetic properties of these compounds can be quantified in vitro with isolated AChE from different origin. It was tempting to evaluate the reactivation kinetics of a series of oximes with various OP inhibitors performed under identical experimental conditions in order to get insight into structural requirements for adequate affinity and reactivity towards inhibited AChE. The determination of reactivation rate constants with bispyridinium oximes having different linkers, bearing oxime group(s) at different positions and having in part additional substituents revealed that (a) the reactivating potency was dependent on the position of the oxime groups and of additional substituents, (b) small modifications of the oxime structure had an in part marked effect on the kinetic properties and (c) no single oxime had an adequate reactivating potency with AChE inhibited by structurally different OP. These and previous studies underline the necessity to investigate in detail the kinetic properties of novel oximes and that the identification of a single oxime being effective against a broad range of structurally different OP will remain a major challenge.
    Keywords: Acetylcholinesterase ; Organophosphorus Compounds ; Oximes ; Kinetics ; Structure–Activity Relationship ; Biology ; Chemistry ; Anatomy & Physiology
    ISSN: 0009-2797
    E-ISSN: 1872-7786
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  • 7
    Language: English
    In: Biochemical Pharmacology, 15 June 2012, Vol.83(12), pp.1700-1706
    Description: Structure–activity-relationship of reactivation kinetics of structurally different oximes with organophosphate-inhibited human acetylcholinesterase. Despite extensive research in the last six decades, oximes are the only available drugs which enable a causal treatment of poisoning by organophosphorus compounds (OP). However, numerous in vitro and in vivo studies demonstrated a limited ability of these oximes to reactivate acetylcholinesterase (AChE) inhibited by different OP pesticides and nerve agents. New oximes were mostly tested for their therapeutic efficacy by using different animal models and for their reactivating potency with AChE from different species. Due to the use of different experimental protocols a comparison of data from the various studies is hardly possible. Now, we found it tempting to determine the reactivation kinetics of a series of bispyridinium oximes bearing one or two oxime groups at different positions and having an oxybismethylene or a trimethylene linker under identical conditions with human AChE inhibited by structurally different OP. The data indicate that the position of the oxime group(s) is decisive for the reactivating potency and that different positions of the oxime groups are important for different OP inhibitors while the nature of the linker, oxybismethylene or trimethylene, is obviously of minor importance. Hence, these and previous data emphasize the necessity for thorough kinetic investigations of OP-oxime-AChE interactions and underline the difficulty to develop a broad spectrum oxime reactivator which is efficient against structurally different OP inhibitors.
    Keywords: Acetylcholinesterase ; Organophosphorus Compounds ; Oximes ; Kinetics ; Structure–Activity Relationship ; Pharmacy, Therapeutics, & Pharmacology ; Chemistry
    ISSN: 0006-2952
    E-ISSN: 1873-2968
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  • 8
    Language: English
    In: PLoS ONE, 01 January 2015, Vol.10(8), p.e0135811
    Description: Standard treatment of poisoning by organophosphorus anticholinesterases uses atropine to reduce the muscarinic effects of acetylcholine accumulation and oximes to reactivate acetylcholinesterase (the effectiveness of which depends on the specific anticholinesterase), but does not directly address the nicotinic effects of poisoning. Bispyridinium molecules which act as noncompetitive antagonists at nicotinic acetylcholine receptors have been identified as promising compounds and one has been shown to improve survival following organophosphorus poisoning in guinea-pigs. Here, we have investigated the structural requirements for antagonism and compared inhibitory potency of these compounds at muscle and neuronal nicotinic receptors and acetylcholinesterase. A series of compounds was synthesised, in which the length of the polymethylene linker between the two pyridinium moieties was increased sequentially from one to ten carbon atoms. Their effects on nicotinic receptor-mediated calcium responses were tested in muscle-derived (CN21) and neuronal (SH-SY5Y) cells. Their ability to inhibit acetylcholinesterase activity was tested using human erythrocyte ghosts. In both cell lines, the nicotinic response was inhibited in a dose-dependent manner and the inhibitory potency of the compounds increased with greater linker length between the two pyridinium moieties, as did their inhibitory potency for human acetylcholinesterase activity in vitro. These results demonstrate that bispyridinium compounds inhibit both neuronal and muscle nicotinic receptors and that their potency depends on the length of the hydrocarbon chain linking the two pyridinium moieties. Knowledge of structure-activity relationships will aid the optimisation of molecular structures for therapeutic use against the nicotinic effects of organophosphorus poisoning.
    Keywords: Sciences (General)
    E-ISSN: 1932-6203
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  • 9
    In: Chemical Communications, 2013, Vol.49(33), pp.3425-3427
    Description: Arrangement of several hydroxamic acid-derived substituents along the cavity of a cyclodextrin ring leads to compounds that detoxify tabun in TRIS-HCl buffer at physiological pH and 37.0 C with half-times as low as 3 min.
    ISSN: 1359-7345
    E-ISSN: 1364-548X
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  • 10
    Language: English
    In: Biophysical Journal, 29 January 2013, Vol.104(2), pp.622a-623a
    Keywords: Biology
    ISSN: 0006-3495
    E-ISSN: 1542-0086
    Source: ScienceDirect Journals (Elsevier)
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