TREATMENT FOR REFRACTORY ANTICHOLINESTERASES.
Final rept. 1 Jul 64-31 Aug 66,
MELPAR FALLS CHURCH VA
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This program was directed toward finding new leads to the synthesis or discovery of compounds which will be useful for the therapy of poison by various anticholinesterase agents. Several inter-related work areas have been investigated simultaneously biochemistry, physical organic chemistry, pharmacology and organic synthesis. The biochemical studies have established a direct kinetic relationship between the loss of reactivatibility of GB -3H inhibited cholinesterases and the formation of free isopropanol -3H. Realkylation studies with diazomethane - 14C on both GD ages enzymes and EA 2192 inhibited cholinesterases indicated that the diazomethane probably realkylated since a low molecular weight radioactive material, tentatively identified as 14C - methyl phosphonic acid was obtained after subsequent nucleophile treatment. Physical organic studies have used p-nitrophenyl methylphosphonate as a model system and have achieved alkylation and displacement when nonaqueous media were used. The pharmacological program has given some evidence that novel reactivators may be found among bisquaternary oxamides. Another aspect of the program showed that such compounds as GB blocked collateral spinal inhibition this may be instrumental in GB - induced spinal convulsions. In the synthesis programs, a number of potential reactivators and intermediates have synthesized. Additional physical-organic studies, which are reported in the Appendix, resulted in the alkylation of sodium p-nitrophenylmethyl-phosphonate with a large number of alkylating agents in dimethylformamide solvent. Differences in rates of hydrolysis of products indicated that a neighboring group mechanism is involved in the solvolytic displacement reaction. Author
- Medicine and Medical Research
- Chemical, Biological and Radiological Warfare