Marks M J, Robinson S F, Collins A C
Institute for Behavioral Genetics, University of Colorado, Boulder, USA.
J Pharmacol Exp Ther. 1996 Jun;277(3):1383-96.
The effects of the nicotinic agonists acetylcholine, (+)-anatox in-a, carbachol, cytisine, dimethylphenylpiperazinum, (+)-epibatidine, (-)-epibatidine, methylcarbachol, D-nicotine, L-nicotine, and tetramethylammonium on 86Rb+ efflux from mouse thalamic synaptosomes were investigated. All 11 agonists evoked a concentration-dependent stimulation of 86Rb+ efflux as well as a time- and concentration-dependent reduction of response (desensitization). The agonists varied widely in potency, efficacy and rate of desensitization. (+)-Epibatidine was the most potent agonist (EC50 = 10 nM), whereas tetramethylammonium was the least potent (EC50 = 65 microM). The agonists containing a quaternary ammonium group were generally more efficacious than the other agonists, except for both of the enantiomers of epibatidine, which stimulated 86Rb+ efflux at least as well as acetylcholine. Cytisine was the least efficacious compound tested with a maximal response approximately 10% that of (-)-epibatidine. Exposure of the thalamic synaptosomes to agonist concentrations that generally stimulated little or no efflux reduced in a concentration-dependent manner a subsequent response to 10 microM nicotine. The IC50 values for this functional blockade (desensitization) were highly correlated with the Ki values for the inhibition of [3H]nicotine binding. Furthermore, exposure of the thalamic synaptosomes to 300 nM L-nicotine reduced the responses evoked by a subsequent exposure to a stimulating concentration of all 11 agonists. The observation of desensitization by both stimulating and substimulating concentrations of each agonist is consistent with the predictions of the two-state model of Katz and Thesleff.
研究了烟碱激动剂乙酰胆碱、（+）-类毒素-a、卡巴胆碱、金雀花碱、二甲基苯基哌嗪、（+）-依博加碱、（-）-依博加碱、甲基卡巴胆碱、D-尼古丁、L-尼古丁和四甲基铵对小鼠丘脑突触体86Rb+外流的影响。所有11种激动剂均引起86Rb+外流的浓度依赖性刺激以及反应的时间和浓度依赖性降低（脱敏）。这些激动剂在效力、效能和脱敏速率方面差异很大。（+）-依博加碱是最有效的激动剂（EC50 = 10 nM），而四甲基铵是效力最低的（EC50 = 65 μM）。除了依博加碱的两种对映体刺激86Rb+外流的效果至少与乙酰胆碱相同外，含有季铵基团的激动剂通常比其他激动剂更有效。金雀花碱是测试的效力最低的化合物，其最大反应约为（-）-依博加碱的10%。将丘脑突触体暴露于通常刺激很少或不引起外流的激动剂浓度下，会以浓度依赖性方式降低随后对10 μM尼古丁的反应。这种功能阻断（脱敏）的IC50值与抑制[3H]尼古丁结合的Ki值高度相关。此外，将丘脑突触体暴露于300 nM L-尼古丁会降低随后暴露于所有11种激动剂的刺激浓度所引发的反应。每种激动剂的刺激浓度和亚刺激浓度均能引起脱敏，这一观察结果与Katz和Thesleff的双态模型预测一致。
