Affinity and phosphonylation constants for the inhibition of cholinesterases by the optical isomers of O-2-butyl S-2-(dimethylammonium)ethyl ethylphosphonothioate hydrogen oxalate |
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| Authors: | DA Wustner TR Fukuto |
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| Institution: | Department of Entomology, Division of Toxicology and Physiology, University of California, Riverside, California 92502 USA |
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| Abstract: | The synthesis of the four optical isomers of known absolute configuration of O-2-butyl S-2-(dimethylammonium)ethyl ethylphosphonothioate hydrogen oxalate is described. Values for the affinity constant (Ka), phosphonylation constant (kp), and bimolecular inhibition rate constant (ki) for the inhibition of bovine erythrocyte acetylcholinesterase, housefly-head acetylcholinesterase, and horse serum cholinesterase by the chiral isomers and the racemic mixture are reported. Using a relatively simple spectrophotometric technique, inhibition times as low as 0.5 sec were used. The phosphorus isomers of Sp configuration were more potent inhibitors than their Rp enantiomers by 1630-fold against the bovine enzyme, 9120-fold against the fly-head enzyme, and 40-fold against the horse serum enzyme. The differences in anticholinesterase activity were attributable to differences in the affinity constant, Ka, and the phosphonylation constant, kp. Small but consistent inhibition rate differences were attributable to asymmetry at carbon. Against horse serum cholinesterase, the SC isomers indicated the presence of three kinetic forms in this enzyme preparation. |
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