Soman and Cyclosarin

Subsequent to the discoveries of GA and GB, soman, also known as GD, was discovered in 1944. Details of the discovery were uncovered by the Soviets, who subsequently produced and stockpiled soman. GD molecules may penetrate the central nervous system within minutes, which makes GD the most toxic of the G-agents. GD is also a colorless liquid at ambient tanperature that evaporates to colorless vapor with 

Cyclosarin, or GF, is another G-agent that contains a fluorine atom. Its IDLH level is 0.03 ppm, similar to GA. GF volatility (438 mg/m ) is higher than that of GA, but much lower than that of GB and GD. 

The abovementioned chemicals are G-agents whose molecules contain phosphorous and either a fluorine (-F) or cyanide (-CN) function group. Molecules of the other group of nerve agents, V-agents, contain both sulfur and phosphorous atoms. 

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The diisopropylfluorophosphatase (DFPase) is found in cephalopod nerve, hepatopancreas and saliva from squid (Anderson et al. 1988). Structurally similar to PONl, the DFPase also is a calcium-containing hydrolase with a six-bladed p-propeUer fold and readily hydrolysis the organophosphate fluoride, diisopropyl-fluorophosphate (DFP), as well as the nerve agents sarin, soman and cyclosarin, in addition to the cyanide-containing OP, the nerve agent tabun (Fig. 3.15). DFPase was initially found to hydrolyze P-F and P-CN bonds and to be inert toward P-0 or P-S bonds (Bigley and Raushel 2013). 

G, J., John, H., Melzer, M., et al., 2010. Stable adducts of nerve agents sarin, soman and cyclosarin with TRIS, TES and related buffers compounds—characterization by LC-ESI-MS/MS and NMR and implications for analytical chemistry. J. Chromatogr. B 878, 1382-1390. 

Other well-known G-nerve agents contain fluor (i.e., sarin, soman, and cyclosarin), whereas tabun contains —CN as a leaving group (Table 57.2, Figure 57.3). However, sarin and soman have one substitution by a P—O—bond, and another has a P=C bond, so they are usually named phosphonates. Phosphoroamidate compoimds have also been synthesized with a non-substituted amido group (P-NH2/ i e., methamidophos)... 

As stated, a number of PBPK/PD models have been developed for individual nerve agents (sarin, VX, soman, and cyclosarin) in multiple species. Chapter 58 in the current volume discusses tiie development of such models. Standalone PBPK or compartmental models have also been developed that describe the pharmacokinetics of certain countermeasures, such as diazepam (Igari et al., 1983 Gueorguieva et al., 2004) and oximes (Stemler et al., 1990 Sterner et al., 2013). However, to date, few models for specific countermeasures have been harmonized and linked to NA PBPK/PD models to be able to quantitatively describe their pharmacokinetic and pharmacodynamic interactions. This is partly due to the fact that most PBPK/ PD models developed for NAs and other OPs focus on the inhibition of ChEs as the critical endpoint. The lack of a mathematical description of the disruption of other complex biochemical pathways presents a problem for linking these NA models to those of many countermeasures. For example, the conventional NA countermeasures, atropine and diazepam, as well as many novel countermeasures, do not directly impact ChE kinetics because they act at sites distinct from the active site of the esterases, such as muscarinic, GABA, or NMDARs (Figure 69.2). 

The chemical warfare (CW) nerve agents primarily addressed in this chapter include the anticholinesterase nerve agents tabun (GA), sarin (GB), soman (GD), cyclosarin (GF), and VX, all of which are, or have been, part of the US domestic munitions inventories (Carnes, 1989 NRC, 1999 Opresko et al, 1998). Russian VX (often represented as VR) will be evaluated in the following chapter by Radilov et al. (2009). Other, less well-characterized nerve agents such as compound GE, VG (Amiton ) or Vx will be evaluated as data allow. 

Organophosphate (OP) nerve agents. These agents are extremely toxic compoimds that work by interfering with the nervous system, and include soman, sarin, cyclosarin, tabun, and VX. 

The recent study of Williams et al (2007) found that sarin, soman, cyclosarin, and tabun phosphylate a tyrosine residue on albumin in human blood. The tyrosine adducts with soman and tabun were detected in guinea pigs receiving therapy 7 days following subcutaneous administration of five times the LD50 dose of the respective nerve agent. VX also forms a tyrosine adduct in human blood in vitro but only at high concentrations. 

FIGURE 19.1 Chemical structures of nerve agents the nerve agents sarin (GB), soman (GD), and cyclosarin (GF) lose fluorine subsequent to binding to cholinesterase. The agents tabun (GA), VX, and Russian VX lose CN, and the thiol groups, respectively. 

FIGURE 19.2 Hydrolysis pathway of sarin (GB), soman (GD), and cyclosarin (GIO hydrolysis pathway of nerve agents proceeds through the alkyl methylphosphonic acids, isopropyl methylphosphonic acid (IMPA), pinacolyl methylphosphonic acid (PMPA), and cyclohexyl methylphosphonic acid (CMPA) to methylphos-ponic acid (MPA). Analysis of the alkyl methylphosphonic acids allows identification of the parent agent, while assay of MPA is nonspecific. 

The three types of nerve agent known to have been weaponized are typified by sarin (GB), VX and tabun (GA). Soman (GD) and cyclosarin (GF) are less volatile phosphonofluo-ridate analogues of sarin, and RVX or R-33 is a Russian analogue of VX with broadly similar properties. Tabun differs from the other nerve agents in that it does not possess a P-methyl substituent, which has important implications for... 

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