Structure-activity relationship of reversible cholinesterase inhibitors: activation, channel blockade and stereospeceficity of the nicotinic acetylcholine receptor-ion channel complex

RESUMO

We have shown that alt 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 inn 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. 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...