<unk> is an acetylcholinesterase inhibitor. It works by blocking the function of the enzyme acetylcholinesterase (AChE). Normally, when a motor neuron is stimulated, it releases the neurotransmitter acetylcholine (ACh) into the space between the neuron and an adjacent muscle cell, the synaptic cleft. When acetylcholine binds to nicotinic receptors at the neuromuscular junction, it stimulates muscle contraction. To avoid a state of constant muscle contraction, the acetylcholine is then broken down (hydrolysed) into the inactive substances acetic acid and choline by AChE.<unk> blocks the action of AChE, resulting in an accumulation of acetylcholine in the space between the neuron and muscle cell. On a molecular level, this leads to the ongoing stimulation and eventual fatigue of all affected muscarinic and nicotinic ACh receptors. This results in initial violent contractions, followed by sustained supercontraction restricted to the fluid (sarcoplasm) of the subjunctional endplate and prolonged, depolarizing neuromuscular blockade.The prolonged blockade results in flaccid paralysis of all the muscles in the body, and it is such sustained paralysis of the diaphragm muscle that causes death by asphyxiation. Accumulation of acetylcholine in the brain also causes neuronal excitotoxicity, due to activation of nicotinic receptors and glutamate release. The extreme toxicity of<unk> is partly due to the fact that the inhibitor was designed to be an excellent structural mimic for the transition state of the natural substrate (acetylcholine) of acetylcholinesterase.<unk> has a very high "on-rate" to react with the target enzyme and form a stable P-O-C bond (phosphorylation). However, compared with other highly toxic nerve agents like soman or sarin,<unk> undergoes relatively slow "aging". Aging is a time-dependent side reaction (loss of an alkoxyl group) that occurs on nerve agents after phosphonylation and renders the nerve agent-acetylcholinesterase complex highly resistant to regeneration by any known antidote. Slower aging by<unk> suggests it should be possible to develop more effective antidotes and treatments. The reaction products of acetylcholinesterase with<unk> before and after the "aging" reaction were solved near atomic resolution by X-ray crystallography to aid in antidote development. The X-ray structures revealed the specific parts of the<unk> molecule that interact with key residues and sub-sites of the target enzyme. The structural kinetic of phosphonylation followed by aging also showed an unexpected conformational change in the catalytic triad suggestive of an "induced fit" between the<unk> molecule and acetylcholinesterase.
VX 
VG 
SmeT
Bra
VistA
Sim4
MVA-B
ReNu