Structure-activity relationships and anticholinesterase activity

Maxwell, Donald M.; Lenz, David E.

doi:10.1016/b978-0-7506-0271-6.50012-7

Cited by 11 publications

(9 citation statements)

References 28 publications

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“…The molecular structure of OP and carbamate pesticides is an important factor in determining their reactivity with AChE [28,29]. The molecular configuration as well as the atomic composition of OPs and carbamates will influence characteristics such as electrophilicity and hydrophobicity, which are directly related with the rate of AChE inhibition [29]. These characteristics also will influence pesticide binding with esterases other than AChE [28].…”

Section: Discussionmentioning

confidence: 99%

A comparative study on the relationship between acetylcholinesterase activity and acute toxicity in Daphnia magna exposed to anticholinesterase insecticides

Printes

Callaghan

2004

Enviro Toxic and Chemistry

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Acetylcholinesterase (AChE) activity was measured in Daphnia magna that had been exposed to four organophosphates (OPs; parathion, chlorpyrifos, malathion, and acephate) and one carbamate (propoxur) for 48 h. These results were related to acute toxicity (median effective concentration [EC50] for immobility). For the four OPs, the EC50s were 7.03 pM, 3.17 pM, 10.56 pM, and 309.82 microM, respectively. The EC50 for propoxur was 449.90 pM. Reduction in AChE activity was directly related to an increase in immobility in all chemicals tested. However, the ratio between the EC50 and the AChE median inhibiting concentration ranged from 0.31 to 0.90. A 50% reduction in AChE activity generally was associated with detrimental effects on mobility. However, for acephate, high levels of AChE inhibition (70%) were observed in very low concentrations and were not associated with immobility. In addition, increasing the concentration of acephate further had a slight negative effect on AChE activity but a strong detrimental effect on mobility. Binding sites other than AChE possibly are involved in acephate toxicity to D. magna. Our findings demonstrate different associations between AChE inhibition and toxicity when different chemicals are compared. Therefore, the value of using AChE activity as a biomarker in D. magna will be dependent on the chemical tested.

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Section: Discussionmentioning

confidence: 99%

A comparative study on the relationship between acetylcholinesterase activity and acute toxicity in Daphnia magna exposed to anticholinesterase insecticides

Printes

Callaghan

2004

Enviro Toxic and Chemistry

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“…It is evident that LD50 of heptenophos is about 10 times higher than in the other two organophosphorus compounds tested. This finding should be ascribed to complex interactions of numerous factors such as electronic effects, hydrophobicity, steric effects, ionic bonds, toxicokinetic properties and non-anticholinesterase effects (Maxwell & Lenz 1992).…”

Section: Resultsmentioning

confidence: 99%

Efficacy of Trimedoxime in Mice Poisoned with Dichlorvos, Heptenophos or Monocrotophos

Antonijević

Bokonjić²,

Stojiljković³

et al. 2005

Basic Clin Pharma Tox

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The aim of the study was to examine antidotal potency of trimedoxime in mice poisoned with three direct dimethoxy-substituted organophosphorus inhibitors. In order to assess the protective efficacy of trimedoxime against dichlorvos, heptenophos or monocrotophos, median effective doses and efficacy half-times were calculated. Trimedoxime (24 mg/kg intravenously) was injected 5 min. before 1.3 LD50 intravenously of poisons. Activities of brain, diaphragmal and erythrocyte acetylcholinesterase, as well as of plasma carboxylesterases were determined at different time intervals (10, 40 and 60 min.) after administration of the antidotes. Protective effect of trimedoxime decreased according to the following order: monocrotophos Ͼ heptenophos Ͼ dichlorvos. Administration of the oxime produced a significant reactivation of central and peripheral acetylcholinesterase inhibited with dichlorvos and heptenophos, with the exception of erythrocyte acetylcholinesterase inhibited by heptenophos. Surprisingly, trimedoxime did not induce reactivation of monocrotophos-inhibited acetylcholinesterase in any of the tissues tested. These organophosphorus compounds produced a significant inhibition of plasma carboxylesterase activity, while administration of trimedoxime led to regeneration of the enzyme activity. The same dose of trimedoxime assured survival of experimental animals poisoned by all three organophosphorus compounds, although the biochemical findings were quite different.

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“…For example, P¼O compounds are generally more potent than P¼S compounds because the greater electronegativity of O weakens the P¼X bond, thereby enhancing binding to acetylcholinesterase; compounds that have longer n-alkyl R groups are generally more potent than those that have shorter n-alkyl groups because their greater hydrophobicity enhances binding to acetylcholinesterase. Compounds that have less bulky R or X groups are generally more potent than those that have bulkier groups hindering interaction with acetylcholinesterase (2,32). Differences in binding affinity for other esterases relative to acetylcholinesterase and in the rate and degree of binding reversibility and aging of phosphorylated acetylcholinesterase also impact potency.…”

Section: Mechanism Of Actionmentioning

confidence: 97%

“…Structural characteristics such as the lability of the P¼X bond and the overall hydrophobicity and steric characteristics of the molecule determine binding affinity (2,32). For example, P¼O compounds are generally more potent than P¼S compounds because the greater electronegativity of O weakens the P¼X bond, thereby enhancing binding to acetylcholinesterase; compounds that have longer n-alkyl R groups are generally more potent than those that have shorter n-alkyl groups because their greater hydrophobicity enhances binding to acetylcholinesterase.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

Organophosphorus Pesticides

Storm¹

2012

Patty's Toxicology

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Most organophosphorus compounds today fall into two general groups: the so‐called nerve agents, that are very acutely toxic and organophosphorus pesticides that are less toxic. Nerve agents were generally the first toxic organophosphorus developed, and were the original basis for organophosphorus pesticides. Interest about nerve agents has increased lately given concerns about their potential use in terrorist acts. Organophosphate nerve agents and pesticides are a highly diverse group of chemicals. They are all characterized by their ability to inhibit the enzyme acetylcholinesterase (AChE) that deactivates the neurotransmitter acetylcholine (ACh). At present, the widest use of organophosphorus compounds is as pesticides, although they have also been used as therapeutic agents, gasoline additives, hydraulic fluids, cotton defoliants, fire retardants, plastic components, growth regulators, and industrial intermediates to a much smaller extent. Compounds in this class are numerous and have been categorized in many ways according to the nature of the substituents. Gallo and Lawryk (1991) [2], for example, categorized them into four main groups I–IV based on the characteristics of the leaving group (X). Group I compounds, phosphorylcholines, have a leaving group that contains a quaternary nitrogen and are among the most potent organophosphates (e.g., Shradan). Group II compounds, fluorophosphates, have a fluoride leaving group and are also generally highly toxic (e.g., diisopropyl fluorophosphate). Group III compounds have leaving groups that contain cyanide or a halogen other than fluoride and are generally less potent than group I or II (e.g., Parathion). Group IV contains most of the organophosphates used as insecticides today. These compounds have alkoxy, alkylthio, aryloxy, arylthio, or heterocyclic leaving groups and a wide variety of other substituents. Another classification scheme is based on the nature of the atoms that immediately surround the central phosphorus atom and results in 14 different categories. According to this scheme, phosphates are the prototype for the entire class and are those compounds where all four atoms that surround the phosphorus atom are oxygen (e.g., dichlorvos, mevinphos). Sulfur‐containing organophosphate compounds (phosphorothioates, phosphorothiolates, phosphorodithioates, and phosphorodithiolates) are far more numerous than phosphates and include well‐recognized organophosphate insecticides such as parathion, diazinon, chlorpyrifos, etc. Other groups contain nitrogen (phosphoramides and phosphorodiamides), nitrogen and sulfur (phosphoramidothionates and phosphoramidothiolates), carbon (phosphonates and phosphinates), or carbon and sulfur (phosphonothionates, phosphonothionothiolates, and phosphinothionates). All aspects of organophosphate chemistry, toxicity, analysis, and exposure potential have been previously and comprehensively reviewed. In addition, information regarding the toxicity of organophosphorus pesticides in particular has expanded greatly in recent years as a result of toxicity data supplied by registrants to the U.S. EPA's Office of Pesticides to support reregistration. These data have been made publicly available by the U.S. EPA on its Internet Web site ( www.epa.gov/pesticides ). The following discussion draws heavily from recent reviews and also includes summaries of relevant toxicity data submitted to, and made available by, the U.S. EPA.

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Structure-activity relationships and anticholinesterase activity

Cited by 11 publications

References 28 publications

A comparative study on the relationship between acetylcholinesterase activity and acute toxicity in Daphnia magna exposed to anticholinesterase insecticides

A comparative study on the relationship between acetylcholinesterase activity and acute toxicity in Daphnia magna exposed to anticholinesterase insecticides

Efficacy of Trimedoxime in Mice Poisoned with Dichlorvos, Heptenophos or Monocrotophos

Organophosphorus Pesticides

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