PROTECTION OF GUINEA-PIGS AGAINST SOMAN POISONING BY PRETREATMENT WITH P-NITROPHENYL PHOSPHORAMIDATES

Several p-nitrophenyl phosphoramidates with the general formula RO(NH2 )P(O)OC6H4-p-NO2, in which R = CH2CH3, CH2CH2F, CH2CHF2, CH2CF3, CH2CH 2CH2CH3, and CH2CH2Cl, as well as (NH2)(2)P(O)OC6H4-p-NO2 were adminis tered intravenously to guinea pigs as pretreatment compounds for prote ction against the lethal effects of 1,2,2-trimethylpropyl methylphosph onofluoridate (soman) poisoning. Administration of phosphoramidates at a dose that produces 30% acetylcholinesterase (AChE) inhibition in th e blood of atropinized guinea pigs at the moment of soman poisoning in creases the subcutaneous LD50 of soman up to almost fivefold depending on which compound was used. A synergistic effect with atropine was ob served. Three of these compounds offered a higher degree of protection against soman poisoning than pyridostigmine. Furthermore, the survivi ng animals pretreated with the two phosphoramidates that provided the highest protective ratio were in a better condition at 24 hr after som an intoxication than those pretreated with pyridostigmine. Due to the limited number of compounds and their different characteristics, it ap peared difficult to demonstrate a relationship between the rate of spo ntaneous reactivation of AChE inhibited by the pretreatment compound a nd the protection against soman. Nevertheless, the results indicate th at a several-fold decrease in the rate of spontaneous reactivation rel ative to that of pyridostigmine may increase the protective ratio agai nst soman. (C) 1996 Academic Press, Inc.