Kinetic analysis of interactions between alkylene-linked bis-pyridiniumaldoximes and human acetylcholinesterases inhibited by various organophosphorus compounds

Timo Wille, Fredrik Ekström, Jong Cheol Lee, Yuan-Ping Pang, Horst Thiermann, Franz Worek

Research output: Contribution to journalArticle

16 Citations (Scopus)

Abstract

The therapeutic approach of organophosphorus compound (OP) intoxications is to reactivate the inhibited enzyme acetylcholinesterase (AChE). Numerous studies demonstrated a limited efficacy of standard oxime-based reactivators against different nerve agents such as tabun and cyclosarin. This emphasizes research for more effective oximes. In the present study, reactivation kinetics of tabun-, sarin-, cyclosarin-, VX- or paraoxon-ethyl-inhibited human AChE (hAChE) with a homologous series of bis-ortho-pyridiniumaldoximes, Ortho-4 - Ortho-9, was investigated with a robot-assisted setting, allowing determination of second-order reactivation rate constants as well as model calculations. The reactivation constants of Ortho-4 - Ortho-9 resulted in marked differences of affinity and reactivity depending on the OP structure and the linker length of the oximes. In general, the KD values decreased with increasing linker length. Reactivity increased from Ortho-4 to Ortho-6 for PXE- and VX-inhibited hAChE and from Ortho-4 to Ortho-7 for GA-inhibited hAChE and decreased again with Ortho-8 and Ortho-9. In contrast, kr decreased with increasing linker length for sarin- and cyclosarin-inhibited hAChE. In view of the pronounced decrease of KD from Ortho-4 to Ortho-9, the kr2 values increased with all tested OP. Hence, the ratios of KI/KD and of KI/kr2 showed that in almost all cases the affinity of Ortho-N to the native hAChE was higher than to OP-inhibited enzyme. Model calculations indicated that Ortho-6 - Ortho-9 could be superior to obidoxime in reactivating tabun-inhibited hAChE. Finally, these data emphasize the need to develop oximes with a higher selective affinity towards OP-inhibited hAChE in order to minimize possible side effects.

Original languageEnglish (US)
Pages (from-to)941-946
Number of pages6
JournalBiochemical Pharmacology
Volume80
Issue number6
DOIs
StatePublished - Sep 2010

Fingerprint

Organophosphorus Compounds
Acetylcholinesterase
Oximes
Kinetics
Sarin
Obidoxime Chloride
Enzymes
Rate constants
Robots
cyclohexyl methylphosphonofluoridate
tabun
Research

Keywords

  • Acetylcholinesterase
  • Kinetics
  • Organophosphorus compounds
  • Oxime
  • Reactivation
  • Structure-activity-relationship

ASJC Scopus subject areas

  • Pharmacology
  • Biochemistry

Cite this

Kinetic analysis of interactions between alkylene-linked bis-pyridiniumaldoximes and human acetylcholinesterases inhibited by various organophosphorus compounds. / Wille, Timo; Ekström, Fredrik; Lee, Jong Cheol; Pang, Yuan-Ping; Thiermann, Horst; Worek, Franz.

In: Biochemical Pharmacology, Vol. 80, No. 6, 09.2010, p. 941-946.

Research output: Contribution to journalArticle

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abstract = "The therapeutic approach of organophosphorus compound (OP) intoxications is to reactivate the inhibited enzyme acetylcholinesterase (AChE). Numerous studies demonstrated a limited efficacy of standard oxime-based reactivators against different nerve agents such as tabun and cyclosarin. This emphasizes research for more effective oximes. In the present study, reactivation kinetics of tabun-, sarin-, cyclosarin-, VX- or paraoxon-ethyl-inhibited human AChE (hAChE) with a homologous series of bis-ortho-pyridiniumaldoximes, Ortho-4 - Ortho-9, was investigated with a robot-assisted setting, allowing determination of second-order reactivation rate constants as well as model calculations. The reactivation constants of Ortho-4 - Ortho-9 resulted in marked differences of affinity and reactivity depending on the OP structure and the linker length of the oximes. In general, the KD values decreased with increasing linker length. Reactivity increased from Ortho-4 to Ortho-6 for PXE- and VX-inhibited hAChE and from Ortho-4 to Ortho-7 for GA-inhibited hAChE and decreased again with Ortho-8 and Ortho-9. In contrast, kr decreased with increasing linker length for sarin- and cyclosarin-inhibited hAChE. In view of the pronounced decrease of KD from Ortho-4 to Ortho-9, the kr2 values increased with all tested OP. Hence, the ratios of KI/KD and of KI/kr2 showed that in almost all cases the affinity of Ortho-N to the native hAChE was higher than to OP-inhibited enzyme. Model calculations indicated that Ortho-6 - Ortho-9 could be superior to obidoxime in reactivating tabun-inhibited hAChE. Finally, these data emphasize the need to develop oximes with a higher selective affinity towards OP-inhibited hAChE in order to minimize possible side effects.",
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AU - Worek, Franz

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AB - The therapeutic approach of organophosphorus compound (OP) intoxications is to reactivate the inhibited enzyme acetylcholinesterase (AChE). Numerous studies demonstrated a limited efficacy of standard oxime-based reactivators against different nerve agents such as tabun and cyclosarin. This emphasizes research for more effective oximes. In the present study, reactivation kinetics of tabun-, sarin-, cyclosarin-, VX- or paraoxon-ethyl-inhibited human AChE (hAChE) with a homologous series of bis-ortho-pyridiniumaldoximes, Ortho-4 - Ortho-9, was investigated with a robot-assisted setting, allowing determination of second-order reactivation rate constants as well as model calculations. The reactivation constants of Ortho-4 - Ortho-9 resulted in marked differences of affinity and reactivity depending on the OP structure and the linker length of the oximes. In general, the KD values decreased with increasing linker length. Reactivity increased from Ortho-4 to Ortho-6 for PXE- and VX-inhibited hAChE and from Ortho-4 to Ortho-7 for GA-inhibited hAChE and decreased again with Ortho-8 and Ortho-9. In contrast, kr decreased with increasing linker length for sarin- and cyclosarin-inhibited hAChE. In view of the pronounced decrease of KD from Ortho-4 to Ortho-9, the kr2 values increased with all tested OP. Hence, the ratios of KI/KD and of KI/kr2 showed that in almost all cases the affinity of Ortho-N to the native hAChE was higher than to OP-inhibited enzyme. Model calculations indicated that Ortho-6 - Ortho-9 could be superior to obidoxime in reactivating tabun-inhibited hAChE. Finally, these data emphasize the need to develop oximes with a higher selective affinity towards OP-inhibited hAChE in order to minimize possible side effects.

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