Centrally acting oximes in reactivation of tabun-phosphoramidated AChE

Zrinka Kovarik, Nikolina MačEk, Rakesh K. Sit, Zoran Radić, Valery V. Fokin, K. Barry Sharpless, Palmer Taylor

Research output: Contribution to journalArticle

45 Citations (Scopus)

Abstract

Organophosphates (OP) inhibit acetylcholinesterase (AChE, EC 3.1.1.7), both in peripheral tissues and central nervous system (CNS), causing adverse and sometimes fatal effects due to the accumulation of neurotransmitter acetylcholine (ACh). The currently used therapy, focusing on the reactivation of inhibited AChE, is limited to peripheral tissues because commonly used quaternary pyridinium oxime reactivators do not cross the blood brain barrier (BBB) at therapeutically relevant levels. A directed library of thirty uncharged oximes that contain tertiary amine or imidazole protonable functional groups that should cross the BBB as unionized species was tested as tabun-hAChE conjugate reactivators along with three reference oximes: DAM (diacetylmonoxime), MINA (monoisonitrosoacetone), and 2-PAM. The oxime RS150D [N-((1-(3-(2-((hydroxyimino)methyl)-1H-imidazol-1-yl)propyl)-1H-1,2, 3-triazol-4-yl)methyl)benzamide] was highlighted as the most promising reactivator of the tabun-hAChE conjugate. We also observed that oximes RS194B [N-(2-(azepan-1-yl)ethyl)-2-(hydroxyimino)acetamide] and RS41A [2-(hydroxyimino)-N-(2-(pyrrolidin-1-yl)ethyl)acetamide], which emerged as lead uncharged reactivators of phosphylated hAChE with other OPs (sarin, cyclosarin and VX), exhibited only moderate reactivation potency for tabun inhibited hAChE. This implies that geometry of oxime access to the phosphorus atom conjugated to the active serine is an important criterion for efficient reactivation, along with the chemical nature of the conjugated moiety: phosphorate, phosphonate, or phosphoramidate. Moreover, modification of the active center through mutagenesis enhances the rates of reactivation. The phosphoramidated-hAChE choline-binding site mutant Y337A showed three-times enhanced reactivation capacity with non-triazole imidazole containing aldoximes (RS113B, RS113A and RS115A) and acetamide derivative (RS194B) than with 2PAM.

Original languageEnglish
Pages (from-to)77-80
Number of pages4
JournalChemico-Biological Interactions
Volume203
Issue number1
DOIs
Publication statusPublished - 25 Mar 2013
Externally publishedYes

Fingerprint

Oximes
Blood-Brain Barrier
Sarin
Tissue
Organophosphonates
Mutagenesis
Organophosphates
Peripheral Nervous System
Neurology
Acetylcholinesterase
Choline
tabun
Phosphorus
Serine
Functional groups
Acetylcholine
Amines
Neurotransmitter Agents
Central Nervous System
Binding Sites

Keywords

  • Butyrylcholinesterase
  • CNS AChE reactivation
  • Hydroxyiminoacetamides
  • Organophosphate intoxication
  • Oxime reactivation
  • Tabun

ASJC Scopus subject areas

  • Toxicology

Cite this

Kovarik, Z., MačEk, N., Sit, R. K., Radić, Z., Fokin, V. V., Barry Sharpless, K., & Taylor, P. (2013). Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. Chemico-Biological Interactions, 203(1), 77-80. https://doi.org/10.1016/j.cbi.2012.08.019

Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. / Kovarik, Zrinka; MačEk, Nikolina; Sit, Rakesh K.; Radić, Zoran; Fokin, Valery V.; Barry Sharpless, K.; Taylor, Palmer.

In: Chemico-Biological Interactions, Vol. 203, No. 1, 25.03.2013, p. 77-80.

Research output: Contribution to journalArticle

Kovarik, Z, MačEk, N, Sit, RK, Radić, Z, Fokin, VV, Barry Sharpless, K & Taylor, P 2013, 'Centrally acting oximes in reactivation of tabun-phosphoramidated AChE', Chemico-Biological Interactions, vol. 203, no. 1, pp. 77-80. https://doi.org/10.1016/j.cbi.2012.08.019
Kovarik Z, MačEk N, Sit RK, Radić Z, Fokin VV, Barry Sharpless K et al. Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. Chemico-Biological Interactions. 2013 Mar 25;203(1):77-80. https://doi.org/10.1016/j.cbi.2012.08.019
Kovarik, Zrinka ; MačEk, Nikolina ; Sit, Rakesh K. ; Radić, Zoran ; Fokin, Valery V. ; Barry Sharpless, K. ; Taylor, Palmer. / Centrally acting oximes in reactivation of tabun-phosphoramidated AChE. In: Chemico-Biological Interactions. 2013 ; Vol. 203, No. 1. pp. 77-80.
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