Complexes oxime-AChE

Oximes bind to AChE as reversible inhibitors and form complexes with AChE either at the acylation (catalytic) site, at the allosteric site, or at both sites of the enzyme and protect AChE from phosphorylation. When the reversible inhibitor binds to the catalytic site, the protection is due to direct competition between OP and reversible inhibitor. Binding of a reversible inhibitor to the allosteric site induces indirect protection of the active site. Differences in the mechanisms of enzyme reactivation and protection demonstrate how stereochemical arrangements of oximes can play a role in the potency of their therapeutic efficacy. Direct pharmacological effects, such as direct reaction with OPs (Van Helden et al., 1996), anticholinergic and sympathomimetic effects may also be relevant for the interpretation of antidotal potency of oximes. 

Sarin-inhibited AChE Pralidoxime Liberated AChE Oxime-inhibitor complex... 

The oxime HI-6 with atropine is reasonably effective against soman regardless of the choice of experimental animals while currently used oximes (pralidoxime and obidoxime) seem to be practically uneffective to protect mammals poisoned with supralethal dose of soman (Table 4). Presented data confirm that soman appears to be one of the most resistant nerve agent to the antidotal treatment because of the rapid aging of soman-phosphonylated AChE and the existence of a soman depot in the poisoned organisms (31, 54, 55). The soman-AChE complexes age very quickly and this fact prevents the oxime-induced reac-... 

The ageing process consists of the monodealkylation of the AChE-nerve agent complex. The loss of an alkyl group produces a conformational change that results in the formation of a very stable agent-enzyme complex which is then resistant to spontaneous hydrolysis and reactivation by oximes. The rate of ageing is dependent... 

Reactivating oximes have been designed to fit optimally into the active site of the enzyme acetylcholinesterase to maximize dephosphyla-tion. This property inevitably implies competition with the substrate of AChE. The K values describing the dissociation constant of the oxime from the substrate-free enzyme is around 300 pM, while the Kn value describing the dissociation constant of the oxime from the enzyme-substrate complex is about one order of magnitude higher (Mast, 1997 Eyer, 2003). That means 10 pM oxime is virtually without effect while 100 pM is expected to inhibit AChE to an appreciable extent. Such a peak concentration may... 

The mechanism of AChE inhibition for the all OP and nerve agents is practically the same—the inhibition via phosphorylation or phosphonylation of the esteratic site of AChE. However, reactivation of inhibited AChE by oximes is different for different nerve agents phosphorylated but reactivata-ble AChE is changed to a nonreactivatable complex. The half-times for this reaction described as dealkylation (F5) are different for various OP/nerve agents (B3, Bll). 

The first 4-6 h are the most critical in acute poisoning with OP pesticides. If there is improvement in symptoms after initial treatment, then the patient is very likely to survive if adequate treatment is continued (IPCS, 1998 Jokanovic, 2009). The duration of effects is determined mainly by the properties of the compoimd its lipo-solubility, the stability of the OP-AChE complex, and whether it is reactivatable after the use of ChE reactivators such as pyridinium oximes. 

---