title: A partial agonist model used in the allosteric modulation of the NMDA receptor.
abstract: 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.
authors.affiliation: Division of Pharmacology, College of Pharmacy, The University of Texas at Austin, 78712-1074, USA. robichon@uthscsa.edu
authors.forename: R
authors.initials: R
authors.lastname: Robichon
authors.forename: P K
authors.initials: PK
authors.lastname: Randall
authors.forename: S W
authors.initials: SW
authors.lastname: Leslie
mesh_terms: D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives / Q000378:metabolism; D000494:Allosteric Regulation; D000818:Animals; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000378:metabolism; D005998:Glycine / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D007736:Kynurenic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D008954:Models, Biological; D011485:Protein Binding / Q000187:drug effects; D011760:Pyrrolidinones / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D011760:Pyrrolidinones; D016194:Receptors, N-Methyl-D-Aspartate; C069052:CGP 39653; D015763:2-Amino-5-phosphonovalerate; C001369:1-hydroxy-3-amino-2-pyrrolidone; D007736:Kynurenic Acid; C066192:5,7-dichlorokynurenic acid; D005998:Glycine