López-Muñoz F, Alamo C, Guerra J A, García-García P
Departamento de Farmacología, Facultad de Medicina, Universidad de Alcalá.Alcalá de Henares, Madrid, España.
Rev Neurol. 2008;47(2):99-106.
The discovery and development of the so-called 'nerve agents' (neurotoxic substances to be used as weapons) took place in the Third Reich, largely thanks to the vast amount of progress being made in pharmacology in Germany at that time, both in academic and industrial terms. Furthermore, successive National Socialist governments set up a collaborative network made up of the academia, the chemical industry and military chiefs that also favoured this line of research.
The first neurotoxic substance to be incorporated into the category of 'chemical warfare agent' did so almost wholly by chance. As part of the work being carried out on organophosphate-type pesticides and insecticides, Gerald Schrader, a chemist at the I.G. Farben company, synthesised tabun (ethyl N,N-dimethylphosphoramidocyanidate) and an incident involving accidental contamination of laboratory staff with this substance highlighted its potential toxicity. The same group of researchers later synthesised another substance with the same properties, sarin (isopropyl methylphosphonofluoridate). Both agents were studied for use as chemical weapons by Wolfgang Wirth. At the same time, a group led by Richard Kuhn, who won the Nobel Prize in Chemistry in 1938, synthesised pinacolyl methylphosphonofluoridate, otherwise known as soman.
Pharmacological studies confirmed that the neurotoxic mechanism of action of these substances was the irreversible inhibition of the enzyme acetylcholinesterase, which is responsible for metabolising acetylcholine. Results also showed that an excess of this neurotransmitter led to a continuous over-stimulation of the cholinergic (nicotinic and muscarinic) receptors, which is what triggers the appearance of the wide range of symptoms of poisoning and their swift fatal effect.
所谓“神经毒剂”（用作武器的神经毒性物质）的发现与研制是在第三帝国时期进行的，这在很大程度上得益于当时德国在药理学领域，无论是学术还是工业方面都取得的巨大进展。此外，历届纳粹政府建立了一个由学术界、化学工业界和军方首脑组成的合作网络，这也推动了这一研究方向。
第一种被纳入“化学战剂”类别的神经毒性物质几乎完全是偶然被发现的。作为对有机磷酸酯类杀虫剂和农药研究工作的一部分，法本公司的化学家杰拉尔德·施拉德合成了塔崩（乙基二甲基磷酰胺氰酸盐），一起涉及实验室工作人员意外接触该物质的事件凸显了其潜在毒性。同一组研究人员后来又合成了另一种具有相同性质的物质沙林（异丙基甲基膦酰氟）。这两种毒剂都由沃尔夫冈·维尔特进行了用作化学武器的研究。与此同时，由1938年获得诺贝尔化学奖的理查德·库恩领导的一个团队合成了频那基甲基膦酰氟，即梭曼。
药理学研究证实，这些物质的神经毒性作用机制是对负责代谢乙酰胆碱的乙酰胆碱酯酶进行不可逆抑制。结果还表明，这种神经递质过量会导致胆碱能（烟碱型和毒蕈碱型）受体持续过度刺激，这就是引发各种中毒症状及其迅速致命效应的原因。
