Study on activity of novel PAM analogues in brain

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K11566
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Emergency medicine
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Sakurada Koichi 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10334228)
• Co-Investigator(Kenkyū-buntansha): 石井 名実子 東京医科歯科大学, 大学院医歯学総合研究科, 特任助教 (10782386) ; 宇都野 創 東京医科歯科大学, 大学院医歯学総合研究科, 特任助教 (60367521)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 急性中毒学

Outline of Final Research Achievements

To develop novel antidotes that is effective for the CNS after sarin poisoning, a series of experimental systems were established, including anesthetic administration, confirmation of acute symptoms after exposure of sarin analog INMP, continuous intravenous administration of the novel PAM analog 4-PAO and atropine, confirmation of changes in symptoms, and measurement of AChE activity in the brain. In the system, MATP + which is considered to have higher AChE selectivity was confirmed to be better than the conventionally used active substrate ATCh. Simultaneously, although it was clarified that MATP + was directly hydrolyzed by oximes, it was suggested that the clinical concentration of antidote did not affect the evaluation of brain activity. However, it was indicated that the oxime concentration should be considered when using MATP +.

Free Research Field

法医学

Academic Significance and Societal Importance of the Research Achievements

サリン等の解毒剤として認可されている2-PAMはBBBをほぼ通過できないことから、脳内の解毒に有効な薬は存在しない。我々は、これまで数十種類の新規PAM類似体を有機合成し、その中で4-PAOが極めて有望であることを明らかにしてきた。本研究では、ラットを用いたin vivo実験として、麻酔投与後、サリン類似体INMP暴露から4-PAOおよびアトロピン連続投与、脳内AChE活性測定までの一連の実験系を確立し、4-PAOが脳内に効果的である可能性を明らかにした学術的および社会的意義は大きいと考える。また、AChE活性基質としてMATP +の新たな性状を明らかにできた点も意義あるものと考える。