Study of blood-brain barrier penetration of synthesized PAM analogues

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The aim of this study is to develop a new antidote that can easily penetrate the blood-brain barrier (BBB) in organophosphate poisoning. We synthesized various alkylated PAM analogues as an antidote for VX or sarin intoxication and tried to determine their AChE reactivation activities by the method of Ellman et al. with modification. However, 2-PAM dose-dependently hydrolyzed an acetylthiocholine iodide (ASCh). The AChE (0.3U) activity inhibited by VX analog increased to approximately 200% of normal levels after a dosage of 5mM 2-PAM. HPLC analysis further clarified that 2-PAM was converted to acetylated 2-PAM with acetic acid produced from ASCh by hydrolysis. Other oximes also showed esterase-like activity, and their strengths were consistent with those of known reactivators of inhibited AChE. These results indicate that much of the previous data obtained with ASCh relating to the effects of oximes must be rechecked. Next, 6 PAM analogues (2-PATB, 3-PATB, 4-PATB, 4-PAPE, 4-PAD, and 4-PAO), which had relatively high reactivation activities to INMP-exposed human erythrocytes, were selected. Their PAM analogues were administered intravenously via the rat tail vein, and their LO_<50> (mg/kg) values were examined. The toxicities of their PAM analogues were stronger than that of 2-PAM. The in vivo rat brain microdialysis technique with LC-MS/MS was used to determine the BBB penetration of PAM analogues. After intravenous dosage of PAM analogues (10% concentration of LD6o), 4-PAPE and 4-PAO appeared in the dialysate. This finding indicates that these PAM analogues can penetrate across the BBB.