Robichon R, Randall P K, Leslie S W
Division of Pharmacology, College of Pharmacy, The University of Texas at Austin, 78712-1074, USA.
Eur J Pharmacol. 1997 Jun 11;328(2-3):255-63. doi: 10.1016/s0014-2999(97)83053-1.
We used a partial agonist model to understand further the allosteric modulation of D,L-(E)-2-amino4-propyl-5-phosphono-3-pentenoic acid ([3H]CGP-39653) binding by glycine, 1-hydroxy-3-amino-2-pyrrolidone (HA-966) and 5,7-dichlorokynurenic acid at the NMDA receptor. Binding of [3H]CGP-39653 was investigated in homogenates of cortex, hippocampus and cerebellum of adult rat. Glycine, HA-966 and 5,7-dichlorokynurenic acid maximally decreased the binding of 10 nM of [3H]CGP-39653 by approximately 50, 40 and 22%, respectively. Glycine, HA-966 and 5,7-dichlorokynurenic acid reduced [3H]CGP-39653 binding with IC50 values of 0.31, 11 and 0.044 microM, respectively. The decrease in [3H]CGP-39653 binding was due to a reduced affinity (Kd) and number of binding sites (Bmax) by all three drugs at concentrations where approximately maximum inhibition was observed. Glycine, HA-966 and 5,7-dichlorokynurenic acid lowered the Bmax by approximately 29, 16 and 10%, respectively, whereas the Kd values were increased by approximately 84, 44 and 32%, respectively, in cortex and hippocampus. There was no change in the binding of [3H]CGP-39653 in the cerebellum. The model used revealed that neither 5,7-dichlorokynurenic acid nor HA-966 had partial agonist characteristics in respect with the allosteric modulation of [3H]CGP-39653 binding. Furthermore, the results showed that brain regions have different pharmacological profiles which may depend on the NMDA receptor subunit composition.
我们使用部分激动剂模型，进一步了解甘氨酸、1-羟基-3-氨基-2-吡咯烷酮（HA-966）和5,7-二氯犬尿氨酸对N-甲基-D-天冬氨酸（NMDA）受体上D,L-(E)-2-氨基-4-丙基-5-膦酰基-3-戊烯酸（[3H]CGP-39653）结合的变构调节作用。在成年大鼠的皮质、海马和小脑匀浆中研究了[3H]CGP-39653的结合情况。甘氨酸、HA-966和5,7-二氯犬尿氨酸分别使10 nM的[3H]CGP-39653的结合量最大降低约50%、40%和22%。甘氨酸、HA-966和5,7-二氯犬尿氨酸降低[3H]CGP-39653结合的IC50值分别为0.31、11和0.044 microM。在观察到近似最大抑制作用的浓度下，所有三种药物使[3H]CGP-39653结合量的降低是由于亲和力（Kd）和结合位点数量（Bmax）减少所致。在皮质和海马中，甘氨酸、HA-966和5,7-二氯犬尿氨酸分别使Bmax降低约29%、16%和10%，而Kd值分别增加约84%、44%和32%。在小脑中，[3H]CGP-39653的结合没有变化。所使用的模型表明，就[3H]CGP-39653结合的变构调节而言，5,7-二氯犬尿氨酸和HA-966均不具有部分激动剂特性。此外，结果表明脑区具有不同的药理学特征，这可能取决于NMDA受体亚基组成。
