Study of a new antidote for nerve gas poisoning brought by chemical terrorism
| Project/Area Number |
16390518
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Emergency medicine
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| Research Institution | National Research Institute of Police Science |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
SAKURADA Koichi National Research Institute of Police Science, First Forensic Science, Chief, 法科学第一部, 室長 (10334228)
YASUDA Jiro National Research Institute of Police Science, First Forensic Science, Chief, 法科学第一部, 室長 (10282518)
OHTA Hikoto National Research Institute of Police Science, Third Forensic Science, Senior researcher, 法科学第三部, 主任研究官 (40392261)
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| Project Period (FY) |
2004 – 2005
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥6,200,000 (Direct Cost: ¥6,200,000)
Fiscal Year 2006: ¥1,800,000 (Direct Cost: ¥1,800,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2004: ¥2,700,000 (Direct Cost: ¥2,700,000)
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| Keywords | Sarin / 2-PAM / INMP / BBB / VX / Soman |
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| Research Abstract |
To develop a new antidote that can be easily penetrate the blood-brain barrier (BBB) in organophosphate poisoning, twenty-three known and novel homologues of 2-, 3- and 4-PAM were synthesized. And, a non-toxic and stable sarin analogue, isopropyl p-nitrophenyl methylphosphonate (INMP), was also synthesized for safe preparation of sarin-exposed acetylcholineesterase (AChE). Fifty percent inhibitory concentration (IC_50) of INMP on 0.01 U human erythrocytes, AChE was 15 nM. Then, the reactivation activities of synthesized PAM analogues to INMP-exposed human erythrocytes AChE were examined. 2-PAM itself showed the best recovery activity, and the activities of 2-PAM analogues were linearly reduced by elongation of the side chain. This could be explained as a result of the decrease of the dissociation constant (pKa) with the increase of lipophilicity of analogues or the increase in steric hindrance due to the side chain that may prevent the reaction of oxime group and inhibited AChE. All th
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e 3-PAM analogues showed low recovery activities in all chain length. In contrast, recovery activities of all the 4-PAM analogues were more than moderate and increased by side-chain elongation. Regarding the side chains of PAM analogues, linear hydrocarbons seemed to be more suitable than branched hydrocarbons seemed to be more suitable than branched hydrocarbons in terms of both activity and availability. On the other hand, all the alkylbenzyl analogues of 2-PAM and some alkylbenzyl analogues of 4-PAM tested showed strong reactivation activities. Next, the BBB penetration of 4-hydroxyiminomethyl-N-decyl pyridinium bromide, 4-hydroxyiminomethyl-N-octyl pyridinium bromide, 2-hydroxyiminomethyl -N-[p-(tert-butyl) benzyl] pyridinium bromide and 2-hydroxyiminomethyl-N-(p-benzyl) pyridinium bromide using a brain microdialysis technique was examined. However, it was not clear because of their strong heart toxicities. Furthermore, to perform the immunohistochemical assy, polyclonal antibodies specific to PAM analogues were produced using 4-hydroxyiminomethyl-N-(7-carboxyhepto-l-yl) pyridinium bromide coupled to Kehol Limpet Hemocyanin (KLH) with EDC/Diaminodipropylamine Immobilization Kit as an immunogen. Less
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Report
(3 results)
Research Products
(2 results)
