YENİ GELİŞTİRİLEN K027 VE K048 OKSİMLERİNİN İN VİTRO REAKTİVASYON POTENSİ

Öz

2003 yılında, K027 ve K048 adlı iki yeni ümit verici asetilkolinesteraz reaktivatörü AChE; EC 3.1.1.7 geliştirilmiştir. Her ikisi de HI-6 ve trimedoxime TMB-4 türevleri olarak tasarlanmıştır. Bunlar birinci piridinhalkasında dördüncü pozisyonda bir oksim grubu, ikinci piridin halkasında dördüncü pozisyonda bir karbomil grubuolmak üzere iki kuarterner piridin halkası içermekte ve sadece iki piridin halkası arasındaki bağlantı halkasınınuzunluğu bakımından farklılık göstermektedirler K027 – üç metilen köprüsü, K048 – dört metilen köprüsü . Buçalışmada, söz konusu reaktivatörlerin sinir gazı tabun GA ile inhibe edilen AchE’ı in vitroolarak tekraraktifleştirme güçleri gösterilmek istenmiştir. Uygun enzim kaynağı olarak sıçan ve insan beyni kolinesterazlarıkullanılmıştır. Bu bulguya dayanarak insanlarla ilgili reaktivasyon testlerinin AChE reaktivite gelişim yöntemlerini deiçermesi gerektiği düşünülmektedir

Anahtar Kelimeler

• Asetilkolinesteraz reaktivatör, asetilkolinesteraz reaktivatör I (K027), asetilkolinesterazreaktivatör II (K048), tabun

IN VITRO REACTIVATION POTENCY OF NEWLY DEVELOPED OXIMES K027 AND K048

Abstract

In 2003, we have developed two promising acetylcholinesterase AChE; EC 3.1.1.7 reactivators – K027 andK048. Both of them were designed as derivatives of HI-6 and trimedoxime TMB-4 . They consist of two quaternarypyridinium rings, one oxime group in the position four at the first pyridinium ring, one carbamoyl group at theposition four at the second pyridinium ring and they differ just in the length of the connection chain between bothpyridinium rings K027 – three-methylene bridge, K048 – four-methylene bridge . In our study, we would like to showtheir potency to reactivate in vitroAChE inhibited by nerve agent tabun GA . We have used rat and human braincholinesterases as the appropriate source of the enzyme. As resulted from this work, there are differences in thecourse of the reactivation process between rat and human species. Owing to this fact, reactivation test with humanspecies should be included in the AChE reactivator developmental process

Keywords

• Acetylcholinesterase reactivator, acetylcholinesterase reactivator I (K027), acetylcholinesterasereactivator II (K048), tabun

References

1. 1. Bajgar J. Organophosphates/nerve agent poisoning: mechanism of action, diagnosis, prophylaxis, and treatment. Adv. Clin. Chem. 2004; 38: 151-216.
2. 2. Cabal J, Bajgar J. Tabun – reappearance 50 years later. Chem. Listy. In Czech.1999; 93: 27-31.
3. 3. Calic M, Lucic Vrdoljak A, Radic B, Jelic D, Jun D, Kuca K, Kovarik Z. In vitro and in vivo evaluation of pyridinium oximes: mode of interaction with acetylcholinesterase, effect on tabun- and soman-poisoned mice and their cytotoxicity. Toxicology, 2006; 219: 85-96.
4. 4. Clement JG, Erhardt N. In vitro oxime-induced reactivation of various molecular forms of soman-inhibited acetylcholinesterase in striated muscle from rat, monkey and human. Arch. Toxicol. 1994; 68: 648-55.
5. 5 . Dawson RM. Review of oximes available for treatment of nerve agent poisoning. J. App. Toxicol. 1994; 1 4: 3 1 7 - 3 1 .
6. 6. Eto M. Organophosphorus pesticides: Organic and Biological Chemistry. CRC Press Inc. Cleveland, p. 1976: 142
7. 7. Kassa J. Review of oximes in the antidotal treatment of poisoning by organophosphorus nerve agents. J. Toxicol. Clin. Toxicol. 2002; 40: 803-16.
8. 8. Kassa J. The influence of oxime and anticholinergic drug selection on the potency of antidotal treatment to counteract acute toxic effects of tabun in mice. Neurotox. Res. 2006; 9:, 59-62.

9. 9. Kassa J, Kunesova G. The influence of antidotal treatment of low-level tabun exposure on cognitive functions in rats using a water maze. Neurotox. Res. 2006; 9: 39-45.
10. 10. Kassa J, Kunesova G. A comparison of the potency of newly developed oximes (K027, K048) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats. J. Appl. Toxicol. 2006, (In Press).
11. 11. Koplovitz I, Menton R, Matthews C, Shutz M, Nalls C, Kelly S. Dose-response effects of atropine and HI- 6 treatment of organophosphorus poisoning in guinea pigs. Drug Chem. Toxicol. 1995; 18: 119-36.
12. 12. Kuãa K, Bielavsk˘ J, Cabal J, Bielavska M. Synthesis of a potential reactivator of acetylcholinesterase -1-(4- hydroxyiminomethylpyridinium)-3-(carbamoylpyridinium) -propane dibromide. Tetrahedron Lett. 2003; 44: 3123-25.
13. 13. Kuãa K, Bielavsk˘ J, Cabal J, Kassa J. Synthesis of a new reactivator of tabun-inhibited acetylcholinesterase. Bioorg. Med. Chem. Lett. 2003; 13: 3545-7.
14. 14. Kuca K, Jun D, Musilek K. Structural requirements of acetylcholinesterase reactivators. Mini-Rev. Med. Chem. 2006; 6: 269-77.
15. 15. Kuca K, Kassa J. A comparison of the ability of a new byispyridinium oxime - 1 - ( 4 - h y d r o x y i m i n o m e t h y l p y r i d i n i u m )- 4-(4-carbamoylpyridinium)butane dibromide and currently used oximes to reactivate nerve agent-inhibited rat brain acetylcholinesterase by in vitro methods. J. Enzyme Inhib. Med. Chem. 2003; 18: 529-35.
16. 16. Kuca K, Cabal J, Kassa J.: In vitro reactivation of sarin-inhibited brain acetylcholinesterase from various species by various oximes. Journal of Enzyme Inhibition and Medicinal Chemistry. 2005; 20(3): 227-32.
17. 17. Marrs TC, Organophosphate poisoning. Pharmacol. Therap. 1993; 58: 51-66.
18. 18. Patoãka J, Kuãa K, Jun D. Acetylcholinesterase: crucial enzyme of human body. Acta Medica (Hradec Kralove) 2004; 47: 215-30.
19. 1 9 . Patocka J, Cabal J, Kuca K, Jun D. Oxime reactivation of acetylcholinesterase inhibited by toxic phosphorus ester: In vitro kinetics and thermodynamics. J. Appl. Biomed. 2 0 0 5; 3: 91-9.
20. 20. Petroianu GA, Arafat K, Kuca K, Kassa J. Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: in vitro reactivation of red blood cell acetylcholinesterase inhibitied by paraoxon. J Appl. Toxicol. 2006; 26: 64-71.
21. 21. Petroianu GA, Nurulain SM, Nagelkerke N, Al-Sultan MAH, Kuca K, Kassa J. Five oximes (K-27, K-33, K-48, BI-6 and methoxime) in comparison with pralidoxime: survival in rats exposed to the organophosphate paraoxon. J. Appl. Toxicol. 2006; 26: 262-8.
22. 22. Worek F, Littig P, Widmann R, Merkel F, Szinicz L. Reappraisal of factors for the evaluation of oximes as reactivators of nerve agent-inhibited human acetylcholinesterase. In: Proceedings of the 7th International Symposium on Protection against CBW agents, pp. 1-6, Stockholm, Sweden. 2001.
23. 23. Worek F, Reiter G, Eyer P, Szinicz L. Reactivation kinetics of acetylcholinesterase from different species inhibited by highly toxic organophosphates. Arch. Toxicol. 2002; 76: 523-9.