cgp-39653 and 1-hydroxy-3-amino-2-pyrrolidone

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.

Topics: 2-Amino-5-phosphonovalerate; Allosteric Regulation; Animals; Cerebellum; Cerebral Cortex; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glycine; Hippocampus; In Vitro Techniques; Kynurenic Acid; Male; Models, Biological; Protein Binding; Pyrrolidinones; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate