Bedford C D, Harris R N, Howd R A, Goff D A, Koolpe G A, Petesch M, Miller A, Nolen H W, Musallam H A, Pick R O
Organic Chemistry Department, SRI International, Menlo Park, California 94025.
J Med Chem. 1989 Feb;32(2):493-503. doi: 10.1021/jm00122a034.
A series of structurally related mono- and bis-1,3-disubstituted 2-[(hydroxyimino)methyl]imidazolium halides were evaluated in vitro for their ability to reactivate electric eel, bovine, and human erythrocyte (RBC) acetylcholinesterases (AChE) inhibited by ethyl p-nitrophenyl methylphosphonate (EPMP) and 3,3-dimethyl-2-butyl methyl-phosphonofluoridate (soman, GD). All new compounds were characterized for (hydroxyimino)methyl acid dissociation constant, nucleophilicity, octanol-buffer partition coefficient, reversible AChE inhibition, and kinetics of reactivation of EPMP-inhibited AChEs. For GD-inhibited AChEs, maximal reactivation was used to compare compounds since rapid phosphonyl enzyme dealkylation "aging" complicated interpretation of kinetic constants. For comparison, we also evaluated three known pyridinium therapeutics, 2-PAM, HI-6, and toxogonin. In vivo evaluation in mice revealed that when selected imidazolium compounds were coadministered with atropine sulfate, they were effective in providing lifesaving protection against both GD and EPMP challenges. This was a major accomplishment in the search for effective anticholinesterase therapeutics--the synthesis and preliminary evaluation of the first new monoquaternary soman antidotes with potencies superior to 2-PAM. Significantly, there was an apparent inverse relationship between in vitro and in vivo results; the most potent in vivo compounds proved to be the poorest in vitro reactivators. These results suggested that an alternative and possibly novel antidotal mechanism of protective action may be applicable for the imidazolium aldoximes. Selected compounds were also evaluated for their inhibition of AChE phosphorylation by GD and antimuscarinic and antinicotinic receptor blocking effects.
对一系列结构相关的单-和双-1,3-二取代的2-[(羟基亚氨基)甲基]咪唑鎓卤化物进行了体外评估，以检测它们使被对硝基苯基甲基膦酸乙酯（EPMP）和3,3-二甲基-2-丁基甲基膦酰氟（梭曼，GD）抑制的电鳗、牛和人红细胞（RBC）乙酰胆碱酯酶（AChE）重新活化的能力。对所有新化合物都进行了（羟基亚氨基）甲基酸解离常数、亲核性、辛醇-缓冲液分配系数、可逆性AChE抑制以及EPMP抑制的AChE重新活化动力学的表征。对于GD抑制的AChE，由于快速的磷酰化酶脱烷基化“老化”使动力学常数的解释变得复杂，因此使用最大重新活化率来比较化合物。为了进行比较，我们还评估了三种已知的吡啶鎓治疗剂，2-PAM、HI-6和氯磷定。在小鼠体内的评估显示，当选择的咪唑鎓化合物与硫酸阿托品共同给药时，它们能有效地提供针对GD和EPMP攻击的救命保护。这是寻找有效的抗胆碱酯酶治疗剂方面的一项重大成就——合成并初步评估了首批效力优于2-PAM的新型单季铵梭曼解毒剂。值得注意的是，体外和体内结果之间存在明显的反比关系；体内最有效的化合物在体外却是最差的重新活化剂。这些结果表明，一种替代性的、可能是新颖的解毒作用机制可能适用于咪唑鎓醛肟。还评估了所选化合物对GD抑制AChE磷酸化的作用以及抗毒蕈碱和抗烟碱受体阻断作用。
