A Comparison of Neuroprotective Efficacy of the Oxime K203 and its Fluorinated Analogue (KR‐22836) with Obidoxime in Tabun‐Poisoned Rats

Abstract

The ability of the newly developed bispyridinium compound K203 and its fluorinated analogue KR-22836 to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the currently available reactivator of acetylcholinesterase-obidoxime. Tabun-induced neurotoxicity and the neuroprotective effects of all tested oximes in combination with atropine in rats poisoned with tabun at a sublethal dose (200 lg ⁄ kg intramuscularly (i.m.); 80% of LD 50 value) were monitored by a functional observational battery at 24 hr after tabun challenge. The results indicate that all tested oximes combined with atropine were able to survive tabun-poisoned rats 24 hr after tabun challenge while one non-treated tabun-poisoned rat died within 24 hr after tabun poisoning. All tested oximes combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisoning but they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. While the ability to reduce tabun-induced acute neurotoxicity of obidoxime and K203 was similar, the neuroprotective efficacy of KR-22836 was slightly higher compared to other tested oximes. Thus, the newly developed fluorinated analogue of K203, called KR-22836, is able to slightly increase the neuroprotective effectiveness of antidotal treatment of acute tabun poisonings compared to K203 and currently available obidoxime.

Pyridinium Oximes with Ortho-Positioned Chlorine Moiety Exhibit Improved Physicochemical Properties and Efficient Reactivation of Human Acetylcholinesterase Inhibited by Several Nerve Agents

“…Additionally, their acute toxicity in mice was lower than for trimedoxime (LD 50 : K048 > K027 > K203). , However, those oximes still lack the propensity for high penetration through the blood–brain barrier (BBB). − Lipophilicity is an important property for centrally active drugs, and fluorination of the oximes has been introduced in the past in an attempt to increase the lipophilic character of the compounds. , Indeed, it was observed that the permeability of fluorinated oximes in parallel artificial membrane permeation assay (PAMPA) increased proportionately to the increase in the number of fluorine atoms in their structure . Moreover, the fluorinated analogue of oxime K203 showed slightly higher neuroprotection when compared to K203 but did not show higher reactivation of brain AChE, which suggests that it may have other pharmacological effects in the central nervous system (CNS) …”

“…21 Moreover, the fluorinated analogue of oxime K203 showed slightly higher neuroprotection when compared to K203 but did not show higher reactivation of brain AChE, which suggests that it may have other pharmacological effects in the central nervous system (CNS). 22 To allow brain AChE reactivation after OP intoxication, uncharged reactivators have been introduced and tested. 23,24 The design of the potent uncharged molecules originated from AChE inhibitors that were coupled with the novel 3-hydroxy-2pyridinealdoxime scaffold as an efficient nucleophile.…”

Mini review on blood–brain barrier penetration of pyridinium aldoximes

“…A prodrug of pralidoxime is pro‐PAM (Bodor et al ., ). In an attempt to improve the antidote efficacy of these compounds, a wide range of PyAls, such as K027, (Kuca et al ., , ), K048 (Kuca et al ., ), K074 (Kuca et al ., , ), K075 (Kuca et al ., 2005), K117 (Kim et al ., ), K127 (Kim et al ., ), K156 (Kuca et al ., , ), K203 (Musilek et al ., , , ) and KR‐22836 (a fluorinated analogue of K203) (Jeong et al ., ; Kassa et al ., , ) were synthesized (Table ).…”