VZL 2006, 75(1):37-40

Influence of Length and Shape of the Connecting Chain of Bisquaternary Acetylcholinesterase Reactivators on Their Potency to Reactivate Enzyme Inhibited by Sarin

Kamil Kuča ORCID...1, Daniel Jun ORCID...1, Kamil Musílek ORCID...2
1 Univerzita obrany, katedra toxikologie Fakulty vojenského zdravotnictví, Hradec Králové
2 Univerzita Karlova v Praze, katedra farmaceutické chemie a kontroly léčiv Farmaceutické fakulty v Hradci Králové

Antidotní přípravky určené pro léčbu intoxikací nervově paralytickými látkami se skládají z anticholinergik (atropin) a reaktivátorů acetylcholinesterázy (AChE) (pralidoxim, obidoxim, methoxim nebo látka HI-6). Vzhledem k tomu, že v současnosti neexistuje univerzální reaktivátor schopný reaktivovat AChE inhibovanou všemi potenciálními nervově paralytickými látkami, vývoj nových účinnějších reaktivátorů stále pokračuje. Za tímto účelem je nutné znát, jak jednotlivé strukturní faktory reaktivátorů ovlivňují jejich reaktivační schopnost. Mezi nejvíce diskutované faktory patří přítomnost a počet oximových skupin, přítomnost a počet kvarterních dusíků, délka a tvar spojovacího řetězce. V této práci bylo in vitro testováno jedenáct reaktivátorů AChE lišících se délkou a tvarem spojovacího řetězce. Jako vhodný zástupce nervově paralytických látek byl použit sarin. Z výsledků vyplývá, že nejvyšší reaktivační schopnosti bylo dosaženo u trimedoximu (54 %) a oximu K074 (54 %). Této reaktivační schopnosti však bylo dosaženo v koncentracích nedosažitelných u člověka v průběhu antidotní terapie (10-3 M). V terapeuticky relevantních koncentracích (10-5 M) se jevily jako nadějné oximy TO 047 (20 %) a TO 033 (28 %).

Keywords: Sarin; Acetylcholinesteráza; Nervově paralytické látky; Reaktivátor; Oxim

Antidotal treatment of nerve agent poisonings consists of anticholinergics (atropine mainly) and acetylcholinesterase (AChE) reactivators (pralidoxime, obidoxime, methoxime or HI-6). Due to the fact that currently available AChE reactivators are not able to reactivate AChE inhibited by all potential nerve agents, the development of new AChE reactivators still continues. For this purpose, the understanding of relationship between structural factors and their influence on the reactivation potency is useful. Especially, presence and number of functional oxime groups, presence and number of quaternary nitrogens, lentgh and shape of the connecting chain are discussed. Eleven AChE reactivators differing in the length and shape of the connecting chain were tested by in vitro methods in this work. Sarin was used as a representative of the nerve agent family. As resulted, the highest reactivation potency was achieved for trimedoxime (54 %) and oxime K074 (54 %). This reactivation potency was, however, obtained at concentration (10-3 M) that is not attainable for human use. Oximes TO 047 and TO 033 seem to be the most potent AChE reactivator tested in this study at concentration (10-5 M) that is relevant for human use.

Keywords: Sarin; Acetylcholinesterase; Nerve agents; Reactivator; Oxime

Received: September 26, 2005; Published: March 1, 2006  Show citation

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Kuča, K., Jun, D., & Musílek, K. (2006). Influence of Length and Shape of the Connecting Chain of Bisquaternary Acetylcholinesterase Reactivators on Their Potency to Reactivate Enzyme Inhibited by Sarin. Vojenské Zdravotnické Listy, 75(1), 37-40
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