A Comparison of the Potency of Newly Developed Oximes (K005, K027, K033, K048) and Currently Used Oximes (Pralidoxime, Obidoxime, HI-6) to Reactivate Sarin-Inhibited Rat Brain Acetylcholinesterase By in Vitro Methods

Abstract

The potency of newly developed and currently used oximes to reactivate sarin-inhibited acetylcholinesterase was evaluated using in vitro methods. A rat brain homogenate was used as a source of acetylcholinesterase. Significant differences in reactivation potency among all tested oximes were observed. Although the ability of newly developed oximes to reactivate sarin-inhibited acetylcholinesterase does not reach the reactivating potency of the oxime HI-6, the oxime K033 seems to be a more efficacious reactivator of sarin-inhibited acetylcholinesterase than other currently available oximes (pralidoxime, obidoxime) at concentrations (10(-5)-10(-4)M) corresponding to recommended doses in vivo. The results of our study also confirm that the reactivation potency of the tested reactivators depends on many factors, such as (1) the number of pyridinium rings, (2) the number of oxime groups and their position, and (3) the length and the shape of the linkage bridge between pyridinium rings.

Synthesis of a novel series of non-symmetrical bispyridinium compounds bearing a xylene linker and evaluation of their reactivation activity against tabun and paraoxon-inhibited acetylcholinesterase

“…The results confirm that the position of hydroxyiminomethyl groups influences the reactivation potency [30 -33]. In this case, compounds bearing oxime groups in positions 3-4 (6, 9, 12) and 3-3 (14,17,20) were almost ineffective, compounds with oxime groups in positions 2-3 (7, 10), 2-4 (8, 11), 2-2 (16, 19) and 4-4 (15,18,21) showed satisfactory reactivation ability against paraoxon-inhibited AChE. Another important factor for reactivation potency is the structure of the connecting chain as was discussed previously [14 -16].…”

“…Moreover, each position of oxime on the pyridinium ring is able to reactivate another type of inhibitor. While position four is more suitable for tabun or pesticide-inhibited AChE, position two is effective against sarin, soman or VXinhibited AChE [19][20][21]. Position three has usually low efficacy due to the dissociation constant at the pH of human blood [19].…”

Reactivation of sarin-inhibited pig brain acetylcholinesterase using oxime antidotes

“…For example, pralidoxime is unable to reactivate tabun-inhibited and cyclosarin-inhibited AChE in vitro and in vivo [6][7][8]. Similar results were obtained for obidoxime.…”

“…Currently the most promising AChE reactivator, oxime HI-6, is the strongest in vitro and in vivo reactivator against almost all of the nerve agents [5,10]. Unfortunately, it has no potency to reactivate tabuninhibited AChE [6,7]. Therefore, the replacement of currently used AChE reactivators with new and more effective oximes is a long-standing goal for the treatment of poisonings associated with highly toxic OPCs.…”

Group Contribution Methods for Estimation of Selected Physico-Chemical Properties of Organic Compounds

“…In comparison with previous cases (estimations of thermophysical properties) authors have only less experimental data for development of model (about 20 for each of cases). Due to their long names and complex chemical structures these compounds in this chapter only are presented as their codes taken from original papers (Kuča & Kassa, 2003;Kuča et al, 2003a;Kuča et al, 2003b;Kuča et al, 2003c;Kuča & Patočka, 2004;Kuča & Cabal, 2004a;Kuča & Cabal, 2004b;Kuča et. al., 2006.…”