Oximes reactivation potencies

TABLE 66.2. Reactivation potencies of five commercially available oximes (Kuca et a ., 2007a)... 

Picha et al. (2005) returned to monopyridinium compounds (35) with a hydroxyiminomethyl group modified in the side-chain, with the aim of improving the nucleophilicity of this group (Figure 66.28). From the eight oximes prepared and tested, none achieved better reactivation potency if compared with pralidoxime, obidoxime, or HI-6 (Picha et al., 2005 Jun et al, 2008). 

Two other oximes (49, 50) are very interesting when considering blood-brain barrier penetration. They have instead only the quaternary nitrogen, the tertiary nitrogen having no charge. Unfortunately, such structure modification decreased their reactivation potency (Oh et al., 2008). 

The other important structural factor is also connected with the oxime group the position of the oxime group at the quaternary pyridinium ring. As can be seen in Table 66.3, there are significant differences in the reactivation potency of the oximes regarding the oxime group position. 

As can be seen, the number of oxime groups does not increase reactivation potency of the potential AChE reactivator. This fact could be cormected with increased size of the AChE reactivator s molecule. Owing to the fact that the main role in the reactivation process has just the first oxime group (with the lowest pKa), the presence of the second oxime group is not so strict. 

TABLE 66.3. Reactivation potency of selected reactivators influenced by oxime group number and position... 

There are stiU efforts being made to compare oxime HL6-7 with HI-6 to see if its activity is comparable or better. Structures of both compounds are almost similar, differing slightly in one added oxime group at position four on the pyridinium ring. However, the reactivation potency of HL6-7 is not much better to perform all the steps, which are needed for introduction to the market. 

Yang, G.Y., Oh, K.A., Park, N.J., Jung, Y.S. (2007). New oxime reactivators connected with CH20(CH2) 0CH2 linker and their reactivation potency for organophosphorus agents-inhibited acetylcholinesterase. Bioorg. Med. Chem. 15 7704-10. 

The ability of pralidoxime, obidoxime and methoxime to reactivate sarin-inhibited AChE in rat diaphragm and brain is relatively low although methoxime seems to be better reactivator of sarin-inhibited AChE in vivo than expected on the basis of its in vitro reactivation potency (23). H oximes (HI-6, HLp-7) are very efficacious reactivators of sarin-inhibited AChE especially in diaphragm (23). However, they also seem to be good reactivators of sarin-inhibited AChE in the central compartment in spite of their quaternary structure that limits their penetration across the blood-brain barrier. 

Milatovic, D., and Vorkapic-Furac, J., 1989. Synthesis of three pyridoxal oxime derivatives and their reactivating potency against phosphylated acetylcholinesterase. Acta Pharmaceutica Jugoslavia. 39 281-287. 

Jeong, H.C., Kang, N.S., Park, N.J., et ak, 2009. Reactivation potency of fluori-nated pyridinium oximes for acetylcholinesterases inhibited by paraoxon organophosphorus agent. Bioorg. Med. Chem. Lett. 19, 1214-1217. 

Oh, K. A., Park, N.J., Park, N.S., et al., 2008. Determination of reactivation potency for DFP- and paraoxon-inhibited acetylcholinesterases by pyridinium oximes. Chem. Biol. Interact. 175, 365-367. 

Jun, D., Musilova, L., Lazenska, H., Kuca, K., Kassa, J., Bajgar, J. (2007). Potency of several oximes to reactivate human acetylcholinesterase and hutyrylcholinesterase inWhited by paraoxon and methyl-paraoxon in vitro. The IXth International Meeting on Cholinesterases. Suzhou, CWna, May 6-10, 2007. Program Book, p. 140. 

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. 

Probably the most discussed factor is the possibility of a broad-spectrum reactivator. Every new oxime could be tested for its broad-spectrum potency. However, the probability of finding such an oxime is low. Alternately, we can use a combination of two oximes. Such an approach was already applied in the former Yugoslavia (Kovacevic et al, 1989a, b) two decades ago. Candidates for this approach should be oxime HI-6 and various other oximes which are applicable in the case of tabun and pesticide poisoning. 

Jun, D., Kuca, K., Picha, J., Koleckar, V., Marek, J. (2008). Potency of novel oximes to reactivate sarin inhibited human cholinesterases. Drug Chem. Toxicol. 31 1-9. 

Kuca, K., Picha, J., Cabal, J., Liska, F. (2004b). Synthesis of the three monopyridinium oximes and evaluation of their potency to reactivate acetylcholinesterase inhibited by nerve agents. J. Appl. Biomed. 2 51-6. 

Odzak, R., Calic, M., Hrenar, T., Primozic, I., Kovarik, Z. (2007). Evaluation of monoquatemary pyridinium oximes potency to reactivate tabun-inhibited human acetylcholinesterase. Toxicology 233 85-96. 

Generally, the ability of currently available oximes including H oximes to reactivate tabun-inhibited AChE in peripheral as well as central compartment is relatively low. On the contrary of other nerve agents, obidoxime has a higher potency to reactivate tabun-inhibited AChE than HI-6 especially in the central compartment (25). 

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