CODE REF AL7CB116

VX
-Nerve Agent-

VX gas : What is the Chemistry behind & Mechanism of action ?

Aymen LABIDI
INSAT, Université de Carthage, Centre Urbain Nord, BP 676, Tunis-Cedex, 1080 Tunis, Tunisia

articleinfo abstract

Article history: VX, short for "venomous agent X", is one of the best known of the V nerve agents and was first discovered at Porton
Written 11 January 2020 Down in England during the early 1950s based on research first done by Dr. Gerhard Schrader, a chemist working for IG
Farben in Germany during the 1930s. Now one of a broader V-series of agents, they are classified as nerve agents and
Keywords: have been used as a chemical weapon in various recorded deadly attacks. VX fatalities occur with exposure to tens of
A. VX Gas milligram quantities via inhalation or absorption through skin; VX is thus more potent than sarin, another nerve agent
A. Venemous agent with a similar mechanism of action. On such exposure, these agents severely disrupt the body's signaling between
C. Inhibitor the nervous and muscular systems, leading to a prolonged neuromuscular blockade, flaccid paralysis of all the muscles
D. Toxicology in the body including the diaphragm, and death by asphyxiation

1. Physical Properties
VX is an odorless and tasteless chiral organophosphorous chemical
with a molecular weight of 267.37 g/mol. Under standard conditions
it is an amber-colored liquid with a boiling point of 298 °C (568 °F),
and a freezing point of −51 °C (−60 °F). Its density is similar to that of
water. It has a log P value of 2.047, meaning it is relatively
hydrophobic with an about 100-fold more partitioning into octanol,
over water. Its low vapor pressure of 0.09 pascals (1.3×10−5 psi) gives
it a low volatility, resulting in a high persistence in the environment.
When weaponized, it can be dispersed as a liquid, aerosol, or as a
mixture with a clay or talc in the form of a thickened agent
2. Mechanism of action
VX is an acetylcholinesterase inhibitor. It works by blocking the function
of 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. When acetylcholine
is taken up by the muscle cell, 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.
VX 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."[This quote needs a citation] 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.[citation needed]

Accumulation of acetylcholine in the brain also causes

neuronal excitotoxicity, due to activation of nicotinic receptors
and glutamate release.

The extreme toxicity of VX 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. VX 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, VX undergoes relatively slow "aging". Aging is a time-dependent side
reaction (loss of an alkoxyl group) that occurs on nerve agents after
Corresponding author. Tel.: 00216 97 53 75 01.

E-mail address aymenlabidi@insat.u-carthage.tn.

phosphonylation and renders the nerve agent-acetylcholinesterase
complex highly resistant to regeneration by any known antidote. Slower
aging by VX suggests it should be possible to develop more effective
antidotes and treatments.
The reaction products of acetylcholinesterase with VX 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 VX molecule that slightly higher than the dose having any effect at all, and the effects of a
interact with key residues and sub-sites of the target enzyme. The
structural kinetic of phosphonylation followed by aging also showe d an
unexpected conformational change in the catalytic triad suggestive of an The median lethal dose (LD50)—the exposure required to kill half of a
"induced fit" between the VX molecule and acetylcholinesterase.
3. Synthesis
VX is chiral at its phosphorus atom. The individual enantiomers are
identified as SP-(−)-VX, and RP-(+)-VX (where the "P" subscript
highlights that the chirality is at phosphorus).
VX is produced via the transester process, which gives
a racemic mixture of the two enantiomers. This entails a series of steps
whereby phosphorus trichloride is methylated to produce methyl
phosphonous dichloride. The resulting material is reacted
with ethanol to form a diester. This is then transesterified with N,N-
diisopropylaminoethanol to produce the mixed phosphonite. Finally,
this immediate precursor is reacted with sulfur to form VX .
Corresponding author. Tel.: 00216 97 53 75 01.
E-mail address aymenlabidi@insat.u-carthage.tn.
4. Medical Aspects
a. Toxicology
VX is a "particularly toxic nerve agent". The potentially fatal dose is only
fatal dose are so rapid that there is little time for treatment .
tested population—as estimated for 70 kg human males via exposure to the
skin is reported to be 5 - 10 mg (0.00035 oz), and the lethal concentration
time (LCt50), measuring the concentration of the vapor or aerosol per
length of time exposed, is estimated for VX to be 10 - 15 mg·min/m3 for
exposure time of two minutes at a minute volume of 15 l (minute volume of
15 l corresponds to slight physical activity like slow walking).
b. Treatment
When treating VX exposure, primary consideration is given to removal of
the liquid agent from the skin, before removal of the individual to an
uncontaminated area or atmosphere. After this, the victim is
decontaminated by washing the contaminated areas with household bleach
and flushing with clean water, followed by removal of contaminated
clothing and further skin decontamination. When possible,
decontamination is completed before the casualty is taken for further
medical treatment.
An individual known to have been exposed to a nerve-agent, or who
exhibits definite signs or symptoms of nerve-agent exposure is
generally given the antidotes atropine and pralidoxime (2-PAM), and
in the case of convulsions an injected sedative/antiepileptic such
as diazepam.
In several nations the nerve agent antidotes are issued for military
personnel in the form of an autoinjector such as the United States
military Mark I NAAK.
Atropine blocks a subset of acetylcholine receptors known as muscarinic
acetylcholine receptors (mAchRs), so that the buildup of acetylcholine
produced by loss of the acetylcholinesterase function has a reduced effect
on their target receptor.[citation needed] 2-PAM reactivates the
acetylcholinesterase enzyme (AChE), thus reversing the effects of
VX.[citation needed] VX and other organophosphates block AChE activity
by binding to and covalently inactivating the enzyme via transfer of
the phosphonate moiety from VX to the active site of AChE; this inactivates
AChE and produces an inactive bybroduct from the remaining portion of
the VX molecule.[citation needed] Pralidoxime (2-PAM) removes this
phosphate group.
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Corresponding author. Tel.: 00216 97 53 75 01.

E-mail address aymenlabidi@insat.u-carthage.tn.