Binding of soman antidotes to acetylcholine receptors

It has been reported that several bis-quaternary compounds not necessarily having an oxime function can be used to treat soman poisoning in mice. The mechanism for this protection is not clear, but it has been proposed that such compounds may act by blocking muscarinic or nicotinic acetylcholine receptors. We have tested thirty-four compounds for muscarinic binding activity, using displacement of tritiated 3-quinuclidinyl benzilate (QNB) as a criterion, and thirty-two compounds for nicotinic binding based on inhibition of alpha-bungarotoxin (BGT) binding. Only sixteen of these compounds were able to displace QNB from rat brain membranes, and only ten of them affected BGT binding. With one exception, all of the effective compounds belonged to a series of bis-pyridinium compounds that are similar in structure to SAD-128. The binding affinities to muscarinic receptors of all these compounds were low compared to atropine. Some of the compounds bound to nicotinic receptors with affinities approaching that of d-tubocurarine. However, there was not a direct correlation between binding affinity and their reported efficacy against soman.