Aceto M D, Awaya H, Martin B R, May E L
Br J Pharmacol. 1983 Aug;79(4):869-76. doi: 10.1111/j.1476-5381.1983.tb10531.x.
Three quaternary methiodides of nicotine were prepared and tested for antinociceptive activity in the mouse tail-flick, mouse phenylquinone and rat tail-flick tests. Following peripheral administration, all three methiodides were inactive in the mouse and rat tail-flick procedures, whereas nicotine was active in both tests, which suggested that nicotine was acting centrally. Quaternization of nicotine did not eliminate antinociceptive activity as demonstrated by the intraventricular injection of the methiodides in mice. Nicotine pyrrolidine and bis methiodides were somewhat more potent than nicotine, whereas nicotine pyridine methiodide was considerably less potent than nicotine in the tail-flick procedure. Systemically administered nicotine pyrrolidine methiodine was approximately one-third as active as nicotine in the mouse phenylquinone test; nicotine pyridine methiodide and nicotine bis methiodide were 100 and 300 times less active, respectively. Hexamethonium partially blocked nicotine and nicotine pyrrolidine methiodide, whereas mecamylamine blocked nicotine completely but nicotine pyrrolidine methiodide partially. Nicotine may have both central and peripheral actions in the mouse phenylquinone test, whereas nicotine pyrrolidine methiodide may have both nicotine and non-nicotine like antinociceptive activity. The radiolabelled methiodides were synthesized and their disposition in body tissues studied. The methiodides were found to penetrate brain poorly (plasma-to-brain ratios greater than 20). The methiodides were metabolized to nicotine to a small extent. This metabolism occurred to a greater extent in mice than in rats.
制备了三种尼古丁季铵甲碘化物，并在小鼠甩尾试验、小鼠苯醌试验和大鼠甩尾试验中测试了它们的抗伤害感受活性。外周给药后，所有三种甲碘化物在小鼠和大鼠甩尾试验中均无活性，而尼古丁在这两种试验中均有活性，这表明尼古丁起中枢作用。如通过向小鼠脑室内注射甲碘化物所证明的，尼古丁的季铵化并未消除其抗伤害感受活性。尼古丁吡咯烷甲碘化物和双甲碘化物在甩尾试验中的效力略高于尼古丁，而尼古丁吡啶甲碘化物的效力则明显低于尼古丁。在小鼠苯醌试验中，全身给药的尼古丁吡咯烷甲碘化物的活性约为尼古丁的三分之一；尼古丁吡啶甲碘化物和尼古丁双甲碘化物的活性分别低100倍和300倍。六甲铵部分阻断尼古丁和尼古丁吡咯烷甲碘化物，而美加明完全阻断尼古丁，但仅部分阻断尼古丁吡咯烷甲碘化物。在小鼠苯醌试验中，尼古丁可能同时具有中枢和外周作用，而尼古丁吡咯烷甲碘化物可能同时具有尼古丁样和非尼古丁样的抗伤害感受活性。合成了放射性标记的甲碘化物，并研究了它们在身体组织中的分布。发现甲碘化物穿透脑组织的能力较差（血浆与脑的比率大于20）。甲碘化物仅在小程度上代谢为尼古丁。这种代谢在小鼠中比在大鼠中更明显。
