Ellis J, Seidenberg M
Department of Psychiatry, University of Vermont, Burlington 05405.
Mol Pharmacol. 1992 Oct;42(4):638-41.
The abilities of gallamine, obidoxime, tetrahydroaminoacridine (THA), and 8-(N,N-diethylamino)octyl-3,4,5-trimethoxybenzoate (TMB-8) to alter the rate of dissociation of N-[3H]methylscopolamine from rat cardiac muscarinic receptors were investigated. All four ligands monotonically slowed the dissociation, with the order of potency gallamine > TMB-8 > THA > obidoxime. There was a dramatic difference in the efficacy of these allosteric modulators. Gallamine, TMB-8, and THA slowed the dissociation of N-methylscopolamine by > 90% at maximally effective concentrations, whereas obidoxime was capable of slowing it by only about 50%. In a manner analogous to the action of a partial agonist, obidoxime was able to partially reverse the effects of the other three modulators. Furthermore, the concentration-dependent effects of combinations of obidoxime and gallamine were in good agreement with the model of competitive interaction between these two ligands. These results provide the first evidence that two muscarinic allosteric modulators interact competitively at a well defined site.
研究了加拉明、双复磷、四氢氨基吖啶（THA）和8-（N，N-二乙氨基）辛基-3,4,5-三甲氧基苯甲酸酯（TMB-8）改变N-[3H]甲基东莨菪碱从大鼠心肌毒蕈碱受体解离速率的能力。所有这四种配体均使解离过程单调减慢，效力顺序为加拉明>TMB-8>THA>双复磷。这些变构调节剂的效能存在显著差异。加拉明、TMB-8和THA在最大有效浓度下可使N-甲基东莨菪碱的解离减慢>90%，而双复磷仅能使其减慢约50%。与部分激动剂的作用方式类似，双复磷能够部分逆转其他三种调节剂的作用。此外，双复磷和加拉明组合的浓度依赖性效应与这两种配体之间竞争性相互作用的模型高度吻合。这些结果首次证明了两种毒蕈碱变构调节剂在一个明确界定的位点上存在竞争性相互作用。
