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Oximes as inhibitors of acetylholinesterase – a structure-activity relationship (SAR) study
Vendula Sepsova, Jana Zdarova Karasova, Filip Zemek, Brian J. Bennion, Kamil Kuca
Language English Country Czech Republic
Digital library NLK
Source
NLK
ROAD: Directory of Open Access Scholarly Resources
from 2011
- MeSH
- Acetylcholinesterase metabolism drug effects MeSH
- Antidotes pharmacology MeSH
- Cholinesterase Inhibitors poisoning MeSH
- Financing, Organized MeSH
- Humans MeSH
- Models, Molecular MeSH
- Oximes pharmacology MeSH
- Structure-Activity Relationship MeSH
- Check Tag
- Humans MeSH
Acetylcholinesterase (AChE) reactivators (oximes) are generally used as antidotes in case of nerve agent poisoning. Because of their affinity to AChE, they may also act as weak inhibitors of AChE. Their inhibition potency against AChE was determined by an in vitro method based on the interaction between AChE and oxime reactivator in the concentration range 10-1 to 10 -8 M. We used eel AChE for these assays. We found that AChE inhibition strongly depends on the oxime structure. The aim of the present study is to describe the structure-activity relationship (SAR) between oxime structure and inhibition of AChE. AChE reactivators tested include both monoquaternary and bisquaternary structures with the oxime group in different positions on the pyridine ring and with changes in the connecting linker in the case of the bisquaternary compounds. We found AChE inhibition to be highest in bisquaternary oximes that have a longer linker length and have the oxime group in the ortho position. Increased AChE inhibition in monoquaternary oximes was highest when the meta position was occupied by the oxime nucleophile. In addition, different substituents in the connecting chain (in case of bisquaternary oximes) modulated their inhibition potency.
Center of Advances Studies Faculty of Military Health Sciences University of Defence Hradec Kralove
Department of Public Health Faculty of Military Health Sciences University of Defence Hradec Kralove
Department of Toxicology Faculty of Military Health Sciences University of Defence Hradec Kralove
References provided by Crossref.org
Literatura
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- $a Acetylcholinesterase (AChE) reactivators (oximes) are generally used as antidotes in case of nerve agent poisoning. Because of their affinity to AChE, they may also act as weak inhibitors of AChE. Their inhibition potency against AChE was determined by an in vitro method based on the interaction between AChE and oxime reactivator in the concentration range 10-1 to 10 -8 M. We used eel AChE for these assays. We found that AChE inhibition strongly depends on the oxime structure. The aim of the present study is to describe the structure-activity relationship (SAR) between oxime structure and inhibition of AChE. AChE reactivators tested include both monoquaternary and bisquaternary structures with the oxime group in different positions on the pyridine ring and with changes in the connecting linker in the case of the bisquaternary compounds. We found AChE inhibition to be highest in bisquaternary oximes that have a longer linker length and have the oxime group in the ortho position. Increased AChE inhibition in monoquaternary oximes was highest when the meta position was occupied by the oxime nucleophile. In addition, different substituents in the connecting chain (in case of bisquaternary oximes) modulated their inhibition potency.
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