Linked Life Data

19715346

Source:http://linkedlifedata.com/resource/pubmed/id/19715346

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
10
pubmed:dateCreated
2009-10-19
pubmed:abstractText
Both G and V type nerve agents possess a center of chirality about phosphorus. The S(p) enantiomers are generally more potent inhibitors than their R(p) counterparts toward acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). To develop model compounds with defined centers of chirality that mimic the target nerve agent structures, we synthesized both the S(p) and the R(p) stereoisomers of two series of G type nerve agent model compounds in enantiomerically enriched form. The two series of model compounds contained identical substituents on the phosphorus as the G type agents, except that thiomethyl (CH(3)-S-) and thiocholine [(CH(3))(3)NCH(2)CH(2)-S-] groups were used to replace the traditional nerve agent leaving groups (i.e., fluoro for GB, GF, and GD and cyano for GA). Inhibition kinetic studies of the thiomethyl- and thiocholine-substituted series of nerve agent model compounds revealed that the S(p) enantiomers of both series of compounds showed greater inhibition potency toward AChE and BChE. The level of stereoselectivity, as indicated by the ratio of the bimolecular inhibition rate constants between S(p) and R(p) enantiomers, was greatest for the GF model compounds in both series. The thiocholine analogues were much more potent than the corresponding thiomethyl analogues. With the exception of the GA model compounds, both series showed greater potency against AChE than BChE. The stereoselectivity (i.e., S(p) > R(p)), enzyme selectivity, and dynamic range of inhibition potency contributed from these two series of compounds suggest that the combined application of these model compounds will provide useful research tools for understanding interactions of nerve agents with cholinesterase and other enzymes involved in nerve agent and organophosphate pharmacology. The potential of and limitations for using these model compounds in the development of biological therapeutics against nerve agent toxicity are also discussed.
pubmed:grant
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
http://linkedlifedata.com/resource/pubmed/chemical/Acetylcholinesterase, http://linkedlifedata.com/resource/pubmed/chemical/Butyrylcholinesterase, http://linkedlifedata.com/resource/pubmed/chemical/Chemical Warfare Agents, http://linkedlifedata.com/resource/pubmed/chemical/Cholinesterase Inhibitors, http://linkedlifedata.com/resource/pubmed/chemical/Organophosphorus Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Organothiophosphorus Compounds, http://linkedlifedata.com/resource/pubmed/chemical/Phosphoric Acid Esters, http://linkedlifedata.com/resource/pubmed/chemical/Sarin, http://linkedlifedata.com/resource/pubmed/chemical/Soman, http://linkedlifedata.com/resource/pubmed/chemical/cyclohexyl methylphosphonofluoridate, http://linkedlifedata.com/resource/pubmed/chemical/methylphosphonothiolate, http://linkedlifedata.com/resource/pubmed/chemical/tabun
pubmed:status
MEDLINE
pubmed:month
Oct
pubmed:issn
1520-5010
pubmed:author
pubmed:issnType
Electronic
pubmed:volume
22
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
1669-79
pubmed:dateRevised
2011-6-6
pubmed:meshHeading
pubmed:year
2009
pubmed:articleTitle
Chemical synthesis of two series of nerve agent model compounds and their stereoselective interaction with human acetylcholinesterase and human butyrylcholinesterase.
pubmed:affiliation
Human BioMolecular Research Institute, San Diego, California 92121, USA.
pubmed:publicationType
Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural