1. We have shown that all
cholinesterase (ChE) inhibitors, in addition to their well-known anti-ChE activity, have multiple effects on the
nicotinic acetylcholine receptor-
ion channel (AChR) macromolecule resulting from interactions with the agonist recognition site and with sites located at the
ion channel component. Activation, competitive antagonism and different types of noncompetitive blockade occurring at similar concentration ranges and contributing in different proportions result in complex and somewhat unpredictable alterations in AChR function. The question is now raised as to how each effect of these compounds contributes to their antidotal property against organophosphorus (OP)
poisoning, and what set of actions makes one reversible ChE inhibitor a better
antidote. Many lines of evidence support the importance of direct interactions with various sites on the AChR: 1) morphological and toxicological studies with (+)
physostigmine showed that anti-ChE activity is not essential to protect animals against toxicity by irreversible ChE inhibitors; 2) (-)
physostigmine is far more effective against OP
poisoning; 3) open channel blockers such as
mecamylamine with no significant anti-ChE activity enhance the protective action of (-)
physostigmine; 4)
neostigmine,
pyridostigmine, (-)
physostigmine and (+)
physostigmine showed qualitatively and quantitatively distinct toxicity and damage to endplate morphology and function. 2. In prophylaxis and during the very early phase of OP
poisoning,
carbamates, especially (-)
physostigmine combined with
mecamylamine and
atropine, could protect almost 100% of the animals exposed to multiple lethal doses of OPs. Electrophysiological data showed that (-)
physostigmine, among several reversible ChE inhibitors, showed greater potency in depressing both endplate current (
EPC) peak amplitude and tau
EPC. Therefore, concerning neuromuscular transmission, it seems that the higher the potency of a
drug in reducing endplate permeability, the better is its protection against OP toxicity. A reversible open channel blockade combined with some agonist property helps to decrease the effect of ACh at its agonist site and to reduce the ion permeability of open channels. It should be pointed out that, during the later phase of OP
poisoning, AChR desensitization should be most prevalent. Thus, a
drug that can remove the AChR from this rather irreversible state to a more reversible blocked state should be a better protector. Indeed,
oximes such
as 2-PAM and a more potent analog,
HI-6, produce multiple alterations in AChR function that comprise increased channel activation and open-channel blockade.(ABSTRACT TRUNCATED AT 400 WORDS)