Nicotinic Receptors as Targets for Nerve Agent Therapy
Organophosphorus nerve agents exert their toxic action by inhibiting acetylcholinesterase, resulting in overstimulation of muscarinic and nicotinic receptors due to the accumulation of acetylcholine at cholinergic synapses. Historically, treatment of nerve agent poisoning has concentrated on the muscarinic effects, generally using the competitive muscarinic antagonist atropine. Due to the high toxicity of many nicotinic antagonists, nicotinic receptors have been largely neglected as targets for therapeutic intervention. Nicotinic effects are treated indirectly, using oximes to reactivate the inhibited enzyme, an approach that is only effective against certain nerve agents. The non-reactivating therapeutic action of certain oximes has been attributed to their anti-nicotinic properties, and novel noncompetitive nicotinic antagonists based on these oximes have recently shown efficacy against nerve agent poisoning in animal studies. The nicotinic antagonist mecamylamine has been reported to have beneficial effects against organophosphorus nerve agent poisoning. A recently synthesised compound, benthiactzine, has both anti-nicotinic and anti-muscarinic activity, and has been shown to afford better protection than atropine against VX and sarin poisoning. Novel nicotinic compounds are now being explored for the treatment of various diseases and it is possible that some of these may be beneficial for the treatment of poisoning by nerve agents.