The Story and Functioning of Nerve Agents


By Mr. Bert Arissen, Chemistry Teacher in Secondary Education and Nuclear Radiation Expert, Hogeschool Utrecht, Netherlands

Organophosphorus-based chemical warfare agents (OP CWAs) are among the most toxic substances we know and, although the Organization for Prohibition of Chemical Weapons in the Hague has in the last 20 years succeeded in destroying 95% of the worldwide stock of chemical weapons, they are a still a threat in 2022. There are several families of these substances which are discussed below. What makes them scary and as a potential weapon of mass destruction attractive is that they deregulate an important part of our neurotransmission and have neither smell nor taste. Therefore, they can enter our body relatively unnoticed via the respiratory, gastrointestinal tracts or via the skin.

In fact the work on this started in Germany in the early 1930’s. While studying insecticides the Germans discovered a very lethal substance which they called Tabun (after Taboo). In 1938 followed Substance 146, later changed in Sarin. They belong tot the so called G- series, associated with Germany. Besides Tabun (GA) and Sarin (GB) this series contains Soman (GD), Ethyl sarin (GE), Chlorosarin (GC) and Cyclosarin (GF).

Sarin Molecule

In the 50’s British military chemists continued research on these agents and created O-Ethyl-S- [2(diisopropylamino)ethyl] also known as VX. V stands for venomous. At that time it was seen as such an important weapon that the Americans were willing to share the secrets of the hydrogen bomb with the British in exchange for the recipe. Besides VX, 4 other organophosphate esters were developed, all belonging tot he V-family. They are called VE, VG, VM and VR. The Russian newcomer Novichok is based on the latter, about which more later.

VX Molecule

First a bit about the workings of all these agents, called nerve agents. In biochemistry we know reversible and irreversible inhibitors. The latter completely flatten enzymes and are therefore dangerous. And the above substances all belong to that category. The enzyme that is paralyzed by them is acetylcholinesterase (AChE). This enzyme normally breaks down the neurotransmitter Acetylcholine, which fulfills a whole range of important functions in our body, such as movement, breathing, heartbeat, production of stomach acid, etc

The AChE active site is composed of a catalytic triad, formed by the amino-acids serine, glutamine and histidine. This trio actually works really nicely together. The alcohol group on serine is not a very strong nucleophile, but it does cooperate with the other two. The resulting alkoxide on serine now becomes a strong nucleophile and will carry out a nucleophilic attack on a carbon atom of the neurotransmitter acetylcholine, so that it is split into acetic acid and choline for reuse.

Acetic acid and choline
Acetylcholine hydrolyse

However, if organophosphates are available, such as the nerve agents, the AChE is blocked and the neural junctions are literally flooded with the neurotransmitter acetylcholine, telling your muscles to contract continuously (cholinergic crisis). So does your heart and lungs and a horrible death follows, mostly by asphyxiation or cardiac arrest.

The chemical that has become a symbol for carrying out political assasinations is Novichok. First work in the SU was done in 1957 under the name FOLIANT at the State Scientific Research Institute for Organic Chemistry and Technology in Moscow. The V-agent they worked on, VR or Substance 33 was an isomere of VX. The mechanisms of action of VX and VR are the same and both can be employed as binary weapons. but VX is more stable and better weaponizable.So the SU worked further on development of more stable Novichoks with the following specifications: undetectable by NATO forces, penetrate a body without noting it and despite application of personal protection measurements, safe in storage and containment and not

mentioned in the list of Chemical Weapons Convention. Thanks to the Russian Chemist Vil Mirzayanov we have insight in the structure of Novichoks and their development under the FOLIANT program. In addition, the German Federal Intelligence Service in the 90’s received a Novichok’ sample from a Russian scientist, which was then analyzed in Sweden. The substance chemical formula and properties were transferred to selected Western NATO countries, which used it in small quantities for CBRN equipment testing: protection against contamination, detection, decontamination and medical means of protection against contamination. So when Novichok was administered to poison Skripal it was clear that this was A-234, an amidine-based Novichok with functional group RC(NR)NR2.

After this assassination attempt, A-234 Novichok was added to the Annex on Chemicals of the CWC and became a Schedule 1A agent, just like the G and V- agents, together with the structurally similar phosphate A-232 and phosphonate A-230.. However, when an attack on Navalny was carried out 2 years later, it turned out to be a Novichok with an extra amine attached to it instead of a alkyl-group, creating a guanidine group, with general formula HNC(NH2)2. This formula was not yet included in the Schedule. It turned out that the coverage of the Novichoks as a group was too narrow, too much was looked at per molecule. A small adjustment meant it was out of scope, exactly as the Russians wanted.

A-262 molecule

So it is recommended to add some more guanidine-based agents to the list, A-242 and A-262 related.

In addition to the Novichoks, it is also important to include the precursors. In 2020 the Australia Group managed to get 22 possible precursors for Novichoks on the list. It turns out that it works. In August this year, customs officers discovered during a raid on various German chemical companies that they had sold precursors fort he production of nerve agents, including Novichoks to the Russian chemical wholesaler Khimmed. This company is in contact with the FSB and various related military laboratories.

Although the AG list appears to be a good start, it is still advisable to include the precursors for Novichoks in list B of the CWC schedules, where they belong. And preferably in larger families instead of separate molecules.

It is claimed that Novichoks are very potent, so Sergei and Yulia Skripal and Alexei Navalny were lucky in that regard that the dose administered was probably too low to kill. The same goes for the Bulgarian arms dealer Emilian Gebrev, his son Hristo and company manager Valentin Takhchiev. They also were victims of a poisoning attack with Novichok and they all narrowly escaped death. Unfortunately, that’s not the case with Dawn Sturgess, who unsuspectingly sprayed perfume on her wrist from a bottle she found and that, in retrospect, contained Novichok. She died.

Antidotes against nerve agents are a few, especially to mention Atropine, a cholinergic antagonist which blocks the muscarine receptors. This has many effects on the body, the most important in this regard may be increase of heart rate. Furthermore to mention Diazepam. This drug, like a few other benzodiazepines is an efficacious anticonvulsant in nerve agent poisoning by increase of the GABA receptor. GABA is a neurotransmitter that reduces action potentials.

Oximes, like Pralidoxime (2-PAM) or diacetyl monoxime (DAM) are cholinesterase- reactivating agents that restore neuromuscular transmission by releasing the organophosphates from AChE. With time however, due to dealkylation of the alkoxyl group the phosphorilation of AChE becomes permanent, a process called aging. This time varies somewhat between the various organophosphates and is, for example, extremely short in Soman.

Carbamates, like Pyridostigmine are competative inhibitors for OP’s, which mean that they also block acetylcholinesterase, but only temporarely. After release AChE spontaneously recovers to break down acetylcholine. So the working here is prophylactic. Problem is the limited dose for save use, but when administered with pyridostigmine antagonizing drugs the dose can be raised. The Czech Army has good experiences with this combination which they use under the brandname PANPAL. Because the Novichoks have some structural similarity with pralidoxime and pyridostigmine it is supposed that these drugs may be less effective against poisoning by Novischok-agents.


Novichoks are organophosphates like the other CWA’s, so we can use gas chromatography, mass spectrometry (GC-MS), biosensor techniques and phosphorus detection techniques. It is important to invest in first responder training, multi agency efforts, being prepared for advanced dispersion methods (electrostatic sprayers) and above all predictive toxicology. For non-state actors it is very difficult to synthesize (new) nerve agents, see the sect Aum in Japan (Sarin). Despite highly trained chemists in the production of nerve agents and substantial financial resources they were plaged by serious leaks and a (fortunately) ineffective product.

This is different with malicious states who will always be looking for small molecular adaptations with potentially large consequences. So even more from “reactive” to “predictive.” Create an extensive library, including clearance levels. Who needs to know what.

Author: Bio

Mr. Bert Arissen is originally an agricultural engineer. In that capacity, he worked from 1991 to 1998 in second-line veterinary medicine, as a zootechnical expert at the Department of Veterinary Epidemiology. From 1998 to the present he works as a chemistry en physics teacher in secondary education. He also has his own company as a nuclear radiation expert. His expertise lies mainly in the field of radiation protection in industrial and medical applications of radiation.

Bert Arissen has worked a lot with organophosphates in the past and knows the risks of exposure from his own experience. That and a chemical accident in which he was involved about 10 years ago motivated him to delve deeper into substances that have a profound effect on our nervous system, including nerve agents and personal protective measures against them.

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