Cholinolytics in the Treatment of Anticholinesterase Poisoning: Iii. The Effects of Quaternization and Alteration of Anionic Function on the Potency of Cholinolytics in the Treatment of Sarin Poisoning

Abstract

Twenty-one quaternary ammonium salts of cholinolytic drugs have been assessed for potency against Sarin poisoning in mice and rats in a treatment using N-methylpyridinium-2-aldoxime methanesulphonate (P-2-S) as a reactivating oxime. Compounds examined included the methylbromides of six cholinolytics of known effectiveness and eight N-alkylbromides of Parpanit. An attempt was also made to assess the effect of different anions in both tertiary and quaternary salts of atropine and Parpanit.None of the quaternary salts exceeded the potency of atropine sulphate by a factor greater than 1.5 in trials with rats when the compounds were examined in combination with P-2-S, although similar tests in mice showed Trasentin methylbromide and Parpanit n-propylbromide to be more than 1.5 times as active as atropine sulphate. In trials where the compounds were used in conjunction with atropine sulphate and P-2-S, 10 raised the activity of atropine in mice by a factor exceeding 1.5, with the highest value (3.6) being obtained with Parpanit methylmethanesulphonate while in the rat trials 16 quaternaries were effective, the greatest increase (7.5-fold) being obtained with Parpanit benzylbromide.No conclusion on the relative effectiveness of quaternary salts versus their tertiary counterparts could be reached since protective capacity of the quaternary salts altered with the species used, the nature of the test, the cholinolytic, the type of alkyl group introduced, and, at least in the case of Parpanit, depended upon the nature of the anionic group present.

The protective actions of some anticholinergic drugs in sarin poisoning

“…Again, however, there must be some peripheral component in their therapeutic action, due presumably to their antimuscarinic activity, because the quatemary atropine methyl nitrate displays some protective action against organophosphate poisoning when used alone or in conjunction with an oxime (Coleman, Little & Bannard, 1963).…”

“…On the other hand, the actions of the anticholinergic drugs seem to be of greatest importance centrally, mainly in protecting the medullary respiratory centre from the depressant effect of anticholinesterases (Douglas & Matthews, 1952). Again, however, there must be some peripheral component in their therapeutic action, due presumably to their antimuscarinic activity, because the quatemary atropine methyl nitrate displays some protective action against organophosphate poisoning when used alone or in conjunction with an oxime (Coleman, Little & Bannard, 1963).…”

Preparation of antidotes for anticholinesterase poisoning. IV. Synthesis and protective effectiveness of 2′-(cis- and trans-2″-hydroxycyclohexyl)aminoethyl 1-phenylcyclopentanecarboxylate hydrochlorides

“…In connection with our continuing studies on the effectiveness of Parpanit (2'-diethylaminoethyl 1-phei~ylcyclopentanecarboxylate hydrochloride) and its analogues as substitutes for, or adjuncts to, atropine in the treatment of rodents which have been poisoned with organophosphorus anticholinesterases (1)(2)(3)(4)(5) it was desired to examine compounds containing a hydroxyl group close to and in known stereochemical relationship with the amino group in Parpanit. To this end the synthesis of compounds of the type 1 and 2 (R = C,H, or H) has been briefly examined and the in vivo protective effectiveness of compounds 1 and 2 (R = H) was determined.…”