Abstract
Standard treatment of poisoning by organophosphorus anticholinesterases uses atropine to reduce the muscarinic effects of acetylcholine accumulation and oximes to reactivate acetylcholinesterase (the effectiveness of which depends on the specific anticholinesterase), but does not directly address the nicotinic effects of poisoning. Bispyridinium molecules which act as noncompetitive antagonists at nicotinic acetylcholine receptors have been identified as promising compounds and one has been shown to improve survival following organophosphorus poisoning in guinea-pigs. Here, we have investigated the structural requirements for antagonism and compared inhibitory potency of these compounds at muscle and neuronal nicotinic receptors and acetylcholinesterase. A series of compounds was synthesised, in which the length of the polymethylene linker between the two pyridinium moieties was increased sequentially from one to ten carbon atoms. Their effects on nicotinic receptor-mediated calcium responses were tested in muscle-derived (CN21) and neuronal (SH-SY5Y) cells. Their ability to inhibit acetylcholinesterase activity was tested using human erythrocyte ghosts. In both cell lines, the nicotinic response was inhibited in a dose-dependent manner and the inhibitory potency of the compounds increased with greater linker length between the two pyridinium moieties, as did their inhibitory potency for human acetylcholinesterase activity in vitro. These results demonstrate that bispyridinium compounds inhibit both neuronal and muscle nicotinic receptors and that their potency depends on the length of the hydrocarbon chain linking the two pyridinium moieties. Knowledge of structure-activity relationships will aid the optimisation of molecular structures for therapeutic use against the nicotinic effects of organophosphorus poisoning.
Highlights
The acute toxicity of organophosphorus (OP) pesticides and nerve agents is a result of inhibition of acetylcholinesterase (AChE), leading to accumulation of acetylcholine (ACh) at both muscarinic and nicotinic acetylcholine receptors; current pharmacotherapy focuses only on the muscarinic component, using the competitive muscarinic antagonist, atropine
We recently synthesised a novel bispyridinium compound which blocks the open ion channel of the muscle-type nicotinic receptor and we demonstrated that this noncompetitive antagonism, as well as reversing the neuromuscular blocking action of nerve agent in vitro, can protect animals against poisoning by nerve agents when used as part of a therapeutic drug combination [13, 14]
We demonstrate that the bis-pyridinium compounds interact with muscle-type nAChRs, and with neuronal nAChRs containing only α and β subunits, and that the strength of the interactions with muscle nicotinic receptor, neuronal nicotinic receptor and acetylcholinesterase all depend on the length of the polymethylene chain linking the two pyridinium moieties
Summary
The acute toxicity of organophosphorus (OP) pesticides and nerve agents is a result of inhibition of acetylcholinesterase (AChE), leading to accumulation of acetylcholine (ACh) at both muscarinic and nicotinic acetylcholine receptors; current pharmacotherapy focuses only on the muscarinic component, using the competitive muscarinic antagonist, atropine. During a period of repetitive (tetanic) stimulation, the force generated by the muscle rapidly fades as the muscle membrane becomes depolarised without a refractory period. Failure of neuromuscular transmission during AChE inhibition is a combination of depolarisation block and receptor desensitisation The interaction between these two processes is apparent after a prolonged period of AChE inhibition, when the ability of a neuromuscular preparation to sustain a tetanic contraction returns slightly. The mechanism of this adaptation is believed to be chronic desensitisation of the postsynaptic nicotinic receptors, which results in a reduction of the endplate potential amplitude and duration [1, 6]. It has even been suggested that agents that accelerate desensitisation at the neuromuscular junction could be useful in the treatment of anticholinesterase poisoning [6]
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