Correlation of the Anticholinesterase Activity of a Series of Organophosphateswith Their Ability to Compete with Agonist Binding to Muscarinic Receptors

摘要

Some compounds that inhibit acetylcholinesterase (AChE) activity compete directlywith 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 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 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. 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.