Meek_2012_Toxicol.Sci_126_525

Reference

Title : Synthesis and in vitro and in vivo inhibition potencies of highly relevant nerve agent surrogates - Meek_2012_Toxicol.Sci_126_525
Author(s) : Meek EC , Chambers HW , Coban A , Funck KE , Pringle RB , Ross MK , Chambers JE
Ref : Toxicol Sci , 126 :525 , 2012
Abstract :

Four nonvolatile nerve agent surrogates, 4-nitrophenyl ethyl dimethylphosphoramidate (NEDPA, a tabun surrogate), 4-nitrophenyl ethyl methylphosphonate (NEMP, a VX surrogate), and two sarin surrogates, phthalimidyl isopropyl methylphosphonate (PIMP) and 4-nitrophenyl isopropyl methylphosphonate (NIMP), were synthesized and tested as acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) inhibitors. These surrogates were designed to phosphorylate cholinesterases with the same moiety as their respective nerve agents, making them highly relevant for the study of cholinesterase reactivators. Surrogates were characterized by liquid chromatography-mass spectrometry and nuclear magnetic resonance. NEMP, PIMP, and NIMP were potent inhibitors of rat brain, skeletal muscle, diaphragm, and serum AChE as well as human erythrocyte AChE and serum BuChE in vitro. PIMP was determined to degrade quickly in aqueous solution, making it useful for in vitro assays only, and NEDPA was not a potent inhibitor of AChE or BuChE in vitro; therefore, these two surrogates were not tested in subsequent in vivo studies. Sublethal dosages (yielding about 80% brain AChE inhibition) were determined for both the stable sarin surrogate, NIMP (0.325 mg/kg ip), and the VX surrogate, NEMP (0.4 mg/kg ip), in adult male rats. Time course studies indicated the time to peak brain AChE inhibition for both NIMP and NEMP to be 1 h postexposure. Both surrogates yielded severe cholinergic signs. These dosages did not require the addition of atropine to prevent lethality, and the rate of AChE aging was slow, making these surrogates useful for reactivation studies both in vitro and in vivo. The surrogates synthesized in this study are potent yet safer to test than nerve agents and are useful tools for initial screening of nerve agent oxime therapeutics.

PubMedSearch : Meek_2012_Toxicol.Sci_126_525
PubMedID: 22247004

Related information

Inhibitor IMP-pNP    PIMP    NEMP    NEDPA

Citations formats

Meek EC, Chambers HW, Coban A, Funck KE, Pringle RB, Ross MK, Chambers JE (2012)
Synthesis and in vitro and in vivo inhibition potencies of highly relevant nerve agent surrogates
Toxicol Sci 126 :525

Meek EC, Chambers HW, Coban A, Funck KE, Pringle RB, Ross MK, Chambers JE (2012)
Toxicol Sci 126 :525