A partial agonist model used in the allosteric modulation of the NMDA receptor.
A partial agonist model used in the allosteric modulation of the NMDA receptor.
复制标题
用于 NMDA 受体变构调节的部分激动剂模型。
DOI：
10.1016/s0014-2999(97)83053-1
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发表时间：
1997
影响因子：
5
通讯作者：
Leslie,SW
中科院分区：
文献类型：
--
作者：
Robichon,R;Randall,PK;Leslie,SW
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5，7-二氯犬尿烯酸对NMDA受体上d，l-（E）-2-氨基-4-丙基-5-膦酰基-3-戊烯酸（[3 H]CGP-39653）结合的变构调节。在成年大鼠皮质、海马和小脑匀浆中研究了[3 H]CGP-39653的结合。甘氨酸、HA-966和5，7-二氯犬尿烯酸分别使10 nM [3 H]CGP-39653的结合最大降低约50%、40%和22%。甘氨酸、HA-966和5，7-二氯犬尿烯酸可降低[3 H]CGP-39653结合，IC 50值分别为0.31、11和0.044 μM。[3 H]CGP-39653结合的降低是由于在观察到约最大抑制的浓度下，所有三种药物的亲和力（Kd）和结合位点数量（Bmax）降低。在皮质和海马中，甘氨酸、HA-966和5，7-二氯犬尿烯酸分别使Bmax降低约29%、16%和10%，而Kd值分别增加约84%、44%和32%。[3 H]CGP-39653在小脑中的结合无变化。所用模型显示，5，7-二氯犬尿烯酸和HA-966在[3 H]CGP-39653结合的变构调节方面均不具有部分激动剂特征。此外，结果表明，大脑区域具有不同的药理学特征，这可能取决于NMDA受体亚基的组成。
We used a partial agonist model to understand further the allosteric modulation of d,l-(E)-2-amino-4-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 IC50values of 0.31, 11 and 0.044 μM, 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 Bmaxby approximately 29, 16 and 10%, respectively, whereas the Kdvalues 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.