In vitro reactivation potency of some acetylcholinesterase reactivators against sarin- and cyclosarin-induced inhibitions

Abstract

In our study, we have tested six acetylcholinesterase (AChE) reactivators (pralidoxime, obidoxime, HI-6, trimedoxime, BI-6 and Hlö-7) for reactivation of sarin- and cyclosarin-inhibited AChE using an in vitro reactivation test. We have used rat brain homogenate as the suitable source of enzyme. All oximes are able to reactivate sarin-inhibited AChE. On the other hand, only HI-6 is able to reactivate satisfactorily cyclosarin-inhibited AChE.

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].…”

A Comparison of the Neuroprotective Efficacy of Newly Developed Oximes (K156, K203) and Currently Available Oximes (Obidoxime, HI-6) in Cyclosarin-poisoned Rats

“…This is due to the fact that the oxime group of both newly synthesized oximes is situated in position 4. The oxime HI-6 having an oxime group in position 2 generally showed markedly higher reactivating and therapeutic efficacy against cyclosarin than other commonly used oximes (6,8,9), although the differences between the neuroprotective efficacy of the oxime HI-6 and other oximes studied are not as high in this study.…”

“…On the other hand, the number of aldoxime groups is not so important. The oxime HI-6 has only one oxime group but it is significantly more efficacious to reactivate cyclosarin-inhibited AChE than bispyridinium oximes with two aldoxime groups, such as obidoxime, methoxime or trimedoxime (6,9). The chain linking the two quaternary nitrogens in bispyridinium oximes exerts a great influence on the reactivating and therapeutic efficacy, although this part of the oxime reactivator molecule does not play any role in the dephosphorylation process.…”

A Comparison of the Neuroprotective Efficacy of Individual Oximes (Hi-6, Trimedoxime, K203) and Their Mixtures (Hi-6 + Trimedoxime, Hi-6 + K203) in Cyclosarin-Poisoned Rats

“…Even the oxime HI-6 that is considered to be the best reactivator of cyclosarin-inhibited AChE (6,9,10,20,21) is not satisfactorily effective oxime for the elimination of cyclosarin-induced neurotoxic signs and symptoms due to low penetration through BBB and low reactivating efficacy in the CNS (6,22). On the other hand, it is known that the oximes may also attentuate nerve agent-induced brain insult via different mechanisms other than AChE reactivation (35).…”