Ward T R, Ferris D J, Tilson H A, Mundy W R
Neurotoxicology Division, Health Effects Research Laboratory, United States Environmental Protection Agency, Research Triangle Park, North Carolina 27711.
Toxicol Appl Pharmacol. 1993 Oct;122(2):300-7. doi: 10.1006/taap.1993.1199.
Some compounds that inhibit acetylcholinesterase (AChE) activity compete directly with quinuclidinyl benzilate (QNB) binding, a muscarinic antagonist which binds to all subtypes equally, and with cis-methyldioxolane (CD), an agonist that binds with high affinity to the M2 subtype of muscarinic receptors. The relationship between inhibition of AChE activity and the capability to affect muscarinic receptors directly has not been systematically explored. The interaction of eight organophosphates with muscarinic receptors was compared to their ability to inhibit AChE activity in vitro in tissue homogenates from rat hippocampus and frontal cortex, two cholinergically enriched areas of the brain. Of the compounds tested only echothiophate competed for [3H]QNB binding and only at concentrations greater than 100 microM. The anticholinesterase compounds were also tested for their ability to compete with a muscarinic receptor agonist, [3H]CD, which binds with high affinity (approximate KD = 3.5 nM) to 10 and 3% of the muscarinic receptors in the frontal cortex and hippocampus, respectively. The anticholinesterase compounds inhibited high-affinity [3H]CD binding up to 80% and the effects were similar in both tissues. Echothiophate and DFP were potent inhibitors of [3H]CD binding, as were the active "oxon" forms of parathion, malathion, and disulfoton. The parent "thio" forms of these insecticides, however, were much less effective in competing for [3H]CD binding. A similar pattern of potency was observed for the inhibition of brain AChE activity. A strong correlation was found between the ability of a compound to inhibit AChE activity and the ability to compete with [3H]CD binding. These data suggest that the biological effects of cholinesterase-inhibiting compounds may be due to more than their ability to inhibit AChE.
一些抑制乙酰胆碱酯酶（AChE）活性的化合物可直接与二苯羟乙酸喹宁酯（QNB）竞争结合，QNB是一种能与所有亚型均等地结合的毒蕈碱拮抗剂，这些化合物还能与顺式甲基二氧戊环（CD）竞争结合，CD是一种对毒蕈碱受体M2亚型具有高亲和力的激动剂。AChE活性抑制与直接影响毒蕈碱受体能力之间的关系尚未得到系统研究。将八种有机磷酸酯与毒蕈碱受体的相互作用与其在大鼠海马体和额叶皮质（大脑中两个胆碱能丰富的区域）的组织匀浆中体外抑制AChE活性的能力进行了比较。在所测试的化合物中，只有碘磷定能与[3H]QNB竞争结合，且仅在浓度大于100微摩尔时才会如此。还测试了抗胆碱酯酶化合物与毒蕈碱受体激动剂[3H]CD竞争结合的能力，[3H]CD分别与额叶皮质和海马体中10%和3%的毒蕈碱受体具有高亲和力（近似解离常数KD = 3.5纳摩尔）。抗胆碱酯酶化合物可将高亲和力的[3H]CD结合抑制高达80%，且在两种组织中的效果相似。碘磷定和二异丙基氟磷酸酯是[3H]CD结合的强效抑制剂，对硫磷、马拉硫磷和乙拌磷的活性“氧类似物”形式也是如此。然而，这些杀虫剂的母体“硫代”形式在竞争[3H]CD结合方面效果要差得多。在抑制脑AChE活性方面也观察到了类似的效价模式。发现化合物抑制AChE活性的能力与竞争[3H]CD结合的能力之间存在很强的相关性。这些数据表明，胆碱酯酶抑制化合物的生物学效应可能不仅仅归因于它们抑制AChE的能力。
