Oximes in organophosphate poisoning: 60 years of hope and despair

Worek, Franz; Thiermann, Horst; Wille, Timo

doi:10.1016/j.cbi.2016.04.032

Cited by 127 publications

(112 citation statements)

References 49 publications

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“…Comparing the affinities of theb ispyridinium salts substituted with lipophilic (type I, Ta ble 5, entries1-9) with those substitutedw ith polar residues of typeII( Table 5, entries [10][11][12][13][14], it becomes clear that replacement of the alkyl substituents with an N-methylpyrrolidinem oiety at the 3-position (2e,P TM0027) or ap olar methoxy group (2a-c,P TM0008-PTM0010) in the 2-, 3-, or 4-positions has an egative influence on binding affinity. The determinedp K i values range from 3.87 AE 0.13 to 3.97 AE 0.04 and are thus at least about half al og unit lower than those found for the tert-butyl-substituted compounds 1a (PTM0002), 1b (PTM0001) and MB327 (pK i = 4.43 AE 0.12 to 4.73 AE 0.03, Table 5, entries 1-3).…”

Section: Biological Evaluationmentioning

confidence: 99%

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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A novel series of 30 symmetric bispyridinium and related N-heteroaromatic bisquaternary salts with a propane-1,3-diyl linker was synthesized and characterized for their binding affinity at the MB327 binding site of nicotinic acetylcholine receptor (nAChR) from Torpedo californica. Compounds targeting this binding site are of particular interest for research into new antidotes against organophosphate poisoning, as therapeutically active 4-tert-butyl-substituted bispyridinium salt MB327 was previously identified as a nAChR re-sensitizer. Efficient access to the target compounds was provided by newly developed methods enabling N-alkylation of sterically hindered or electronically deactivated heterocycles exhibiting a wide variety of functional groups. Determination of binding affinities toward the MB327 binding site at the nAChR, using a recently developed mass spectrometry (MS)-based Binding Assay, revealed that several compounds reached affinities similar to that of MB327 (pK =4.73±0.03). Notably, the newly prepared lipophilic 4-tert-butyl-3-phenyl-substituted bispyridinium salt PTM0022 (3 h) was found to have significantly higher binding affinity, with a pK value of 5.16±0.07, thus representing considerable progress toward the development of more potent nAChR re-sensitizers.

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Section: Biological Evaluationmentioning

confidence: 99%

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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“…The resulting variability in oxime efficacy has contributed to something of a controversy in the field, with some investigators endorsing the use of oximes for the treatment of poisoning by certain OPs and others concluding that, regardless of the OP, oximes provide no therapeutic benefit at all (reviewed in [21, 22]). Unfortunately, little is known about oxime-assisted reactivation of AChE inhibited by PHO.…”

Section: 0 Introductionmentioning

confidence: 99%

Kinetic analysis of oxime-assisted reactivation of human, Guinea pig, and rat acetylcholinesterase inhibited by the organophosphorus pesticide metabolite phorate oxon (PHO)

Moyer

McGarry

Babin

et al. 2018

Pesticide Biochemistry and Physiology

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Phorate is a highly toxic agricultural pesticide currently in use throughout the world. Like many other organophosphorus (OP) pesticides, the primary mechanism of the acute toxicity of phorate is acetylcholinesterase (AChE) inhibition mediated by its bioactivated oxon metabolite. AChE reactivation is a critical aspect in the treatment of acute OP intoxication. Unfortunately, very little is currently known about the capacity of various oximes to rescue phorate oxon (PHO)-inhibited AChE. To help fill this knowledge gap, we evaluated the kinetics of inhibition, reactivation, and aging of PHO using recombinant AChE derived from three species (rat, guinea pig and human) commonly utilized to study the toxicity of OP compounds and five oximes that are currently fielded (or have been deemed extremely promising) as anti-OP therapies by various nations around the globe: 2-PAM Cl, HI-6 DMS, obidoxime Cl2, MMB4-DMS, and HLö7 DMS. The inhibition rate constants (k i) for PHO were calculated for AChE derived from each species and found to be low (i.e., 4.8 × 103 to 1.4 × 104 M−1 min−1) compared to many other OPs. Obidoxime Cl2 was the most effective reactivator tested. The aging rate of PHO-inhibited AChE was very slow (limited aging was observed out to 48 hours) for all three species. Conclusions: (1) Obidoxime Cl2 was the most effective reactivator tested. (2) 2-PAM Cl, showed limited effectiveness in reactivating PHO-inhibited AChE, suggesting that it may have limited usefulness in the clinical management of acute PHO intoxication. (3) The therapeutic window for oxime administration following exposure to phorate (or PHO) is not limited by aging.

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“…Since then, such chemicals have been repeatedly used in warfare as well as in terrorist attacks . OPCs still cause high numbers of annual fatalities, mostly due to pesticide self‐poisoning . Hence, there is an urgent need for an effective medical treatment to counteract OPC intoxication.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of a Series of Non‐Symmetric Bispyridinium and Related Compounds and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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The current standard therapy to counteract organophosphate intoxication is not effective in equal measure against all types of organophosphorus compounds (OPCs), as the outcome of oxime‐induced reactivation of inactivated acetylcholinesterase (AChE) strongly depends on the particular OPC. In case the reactivation is insufficient, acetylcholine concentrations that rise to pathophysiological levels force the nicotinic acetylcholine receptor (nAChR) into a desensitized state and hence a functionally inactive state. As a consequence, neurotransmission is irreversibly disrupted at the neuromuscular junction. Previous electrophysiological studies identified the symmetric bispyridinium compound 1,1′‐(propane‐1,3‐diyl)bis[4‐(tert‐butyl)pyridin‐1‐ium] diiodide (MB327) as a re‐sensitizer of the desensitized nAChR. MB327 is thereby capable of restoring the functional activity. Very recently, in silico modeling studies suggested non‐symmetric derivatives of MB327 as potential re‐sensitizers with enhanced binding affinity and thus possible enhanced efficacy. In this study, 26 novel non‐symmetric bispyridinium compounds and related derivatives were synthesized. For the synthesis of the highly polar target compounds in sufficient quantities, newly developed and highly efficient two‐step procedures were used. Compounds were characterized in terms of their binding affinity toward the MB327 binding site at the nAChR using recently developed mass spectrometry (MS) Binding Assays. Regarding structure–affinity relationships at the MB327 binding site, the presence of two quaternary aromatic nitrogen centers as well as pyridinium systems with a tert‐butyl group at the 4‐position or a NMe2 group at the 3‐ or 4‐positions appeared to be beneficial for high binding affinities.

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Oximes in organophosphate poisoning: 60 years of hope and despair

Cited by 127 publications

References 49 publications

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

Kinetic analysis of oxime-assisted reactivation of human, Guinea pig, and rat acetylcholinesterase inhibited by the organophosphorus pesticide metabolite phorate oxon (PHO)

Synthesis of a Series of Non‐Symmetric Bispyridinium and Related Compounds and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

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