[3H]CGP 39653: a new N-methyl-D-aspartate antagonist radioligand with low nanomolar affinity in rat brain

Sills, Matthew A.; Fagg, Graham E.; Pozza, Mario F.; Angst, Christof; Brundish, Derek E.; Hurt, Stephen D.; Wilusz, E. J.; Williams, Michael

doi:10.1016/0014-2999(91)90063-v

Cited by 208 publications

(127 citation statements)

References 12 publications

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“…Our finding that [ 3 H]AMPA binding to the AMPA receptors is not changed in BA 9 from subjects with schizophrenia is in agreement with a number of previous studies in that region (Dean et al, 2001;Toru et al, 1988), the prefrontal cortex (BA 9, 11, 32, and 46) (Healy et al, 1998), and frontal cortex (region not specified) (Freed et al, 1993), although one study has reported an increase in the receptor in BA 46 with schizophrenia (Noga et al, 2001). Our study is novel in that cortical NMDA receptor density was measured using two radioligands, one of which binds within the ion channel ([ 3 H]MK-801) (Wong et al, 1986) of the receptor while the other binds to the glutamate binding site on the receptor ([ 3 H]CGP39653) (Sills et al, 1991). The binding of neither radioligand was altered in schizophrenia, which is in agreement with a number of earlier studies (Dean et al, , 2001Kornhuber et al, 1989;Noga et al, 2001) (region not specified in the Kornhuber study).…”

Section: Discussionmentioning

confidence: 99%

“…As discussed previously (Scarr et al, 2003), all binding studies were of the single-point saturation design, where all available receptor sites are occupied by radioligand because the binding of each radioligand was measured at a concentration at least three times that of the K D of the ligand for the receptor of interest (Hoffman et al, 1997;Nishikawa et al, 1983;Piggott et al, 1992;Sills et al, 1991).…”

Section: In Situ Radioligand Bindingmentioning

confidence: 99%

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Cortical Glutamatergic Markers in Schizophrenia

Scarr

Beneyto

Meador‐Woodruff

et al. 2005

Neuropsychopharmacol

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Post-mortem studies have yet to produce consistent findings on cortical glutamatergic markers in schizophrenia; therefore, it is not possible to fully understand the role of abnormal glutamatergic function in the pathology of the disorder. To better understand the changes in cortical glutamatergic markers in schizophrenia, we measured the binding of radioligands to the ionotropic glutamate H]CGP39653 binding did not differ between the diagnostic cohorts. Levels of mRNA for the GluR5 subunit were decreased overall (po0.05), with no changes in levels of mRNA for GluR6, GluR7, KA1, or KA2 in tissue from subjects with schizophrenia. These data indicate that the decreased number of kainate receptors in the dorsolateral prefrontal cortex in schizophrenia may result, in part, from reduced expression of the GluR5 receptor subunits.

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Section: Discussionmentioning

confidence: 99%

Section: In Situ Radioligand Bindingmentioning

confidence: 99%

Cortical Glutamatergic Markers in Schizophrenia

Scarr

Beneyto

Meador‐Woodruff

et al. 2005

Neuropsychopharmacol

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“…Affinities for native AMPA, KA, and NMDA receptors in rat cortical synaptosomes were determined using 5 nM (RS)- (30), respectively, with minor modifications as previously described (31,32).…”

Section: Pharmacologymentioning

confidence: 99%

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Larsen

Venskutonytė

Valadés

et al. 2010

ACS Chem. Neurosci.

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The kainic acid (KA) receptors belong to the class of glutamate (Glu) receptors in the brain and constitute a promising target for the treatment of neurological and/ or psychiatric diseases such as schizophrenia, major depression, and epilepsy. Five KA subtypes have been identified and named GluK1-5. In this article, we present the discovery of (2S,3R)-3-(3-carboxyphenyl)-pyrrolidine-2-carboxylic acid (1) based on a rational design process. Target compound 1 was synthesized by a stereoselective strategy in 10 steps from commercially available starting materials. Binding affinities of 1 at native ionotropic Glu receptors were determined to be in the micromolar range (AMPA, 51 μM; KA, 22 μM; NMDA 6 μM), with the highest affinity for cloned homomeric KA receptor subtypes GluK1,3 (3.0 and 8.1 μM, respectively). Functional characterization of 1 by two electrode voltage clamp (TEVC) electrophysiology at a nondesensitizing mutant of GluK1 showed full competitive antagonistic behavior with a K b of 11.4 μM.

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“…Abbreviations: CA1, CA2, and CA3: fields CA1, CA2, and CA3 of hippocampus; DG: dentate gyrus. (Sills et al 1991), whereas [ 3 H]Ro 25-6981 has more affinity to the polyamine site (Fischer et al 1997). Our results are in agreement with a previous report showing no effect of estradiol on L-[ 3 H]CGP 39653 specific binding in the hippocampal regions of ovariectomized rats (Weiland 1992).…”

Section: Nmda Receptors Mrna Levelsmentioning

confidence: 99%

Estrogen-like Activity of Tamoxifen and Raloxifene on NMDA Receptor Binding and Expression of its Subunits in Rat Brain

Cyr

Thibault

Morissette

et al. 2001

Neuropsychopharmacology

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Hormonal specificity of modulation of N-methyl-D-aspartate (NMDA) receptors was investigated by comparing the effects of estradiol with tamoxifen or raloxifene, which display different responses in breast, bone, and uterus. Two weeks ovariectomy in rats decreasedIt has been shown that the female sex steroid estradiol exerts profound effects on neuronal differentiation during development (Toran-Allerand et al. 1983) and recently, accumulating evidence support also a modulatory role of estrogens in the normal maintenance of brain function during aging (Simpkins et al. 1994). Beneficial effects of estradiol in mood disorders (i.e., depression, pre-menstrual syndrome, post-natal depression), as well as mental diseases, such as schizophrenia and Gille de la Tourette's syndrome, have been reported (Di Paolo 1994;Fink et al. 1998). Moreover, a beneficial role of estradiol in neurodegenerative disFrom the Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, (CHUL), and Faculty of Pharmacy, Laval University, Sainte-Foy, Quebec, Canada, G1V 4G2.Address correspondence to: Dr. Thérèse Di Paolo, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, CHUQ, 2705, Laurier Boulevard, Sainte-Foy, Quebec, Canada G1V 4G2.Received July 5, 2000; revised December 20, 2000; accepted January 3, 2001. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 2 SERMs Modulate NMDA Receptors 243 eases, such as Alzheimer has been recently suggested (Tang et al. 1996;Henderson 1997;Inestrosa et al. 1998). However, the mechanisms by which these effects of estrogens are yet to be fully characterized. N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptor, have been implicated, as mediators, in some effects of estradiol on morphological plasticity and related physiological and cognitive processes in the brain (Moriyoshi et al. 1991). However, only few studies have directly investigated the role of estradiol in regulating NMDA receptors in rat and, in addition, these studies have focused on the effects of estradiol on hippocampal NMDA receptors (Woolley and McEwen 1992;Gazzaley et al. 1996;Woolley et al. 1997). We have recently investigated the effects of estradiol on the NMDA receptors agonist sites in brain regions implicated in mental disorders, such as frontal cortex, striatum, and nucleus accumbens (Cyr et al. 2000a). Our experiments showed that ovariectomy, as well as estradiol have regional specific effects since, for example, ovariectomy decreases NMDA receptor specific binding in hippocampal CA1 and dentate gyrus regions, whereas it has no effect in frontal cortex. In contrast, estradiol increases NMDA specific binding in the hippocampal CA1 and the dentate gyrus, but it decreases this binding in the frontal cortex (Cyr et al. 2000a).The present study sought to determine whether changes observed previously at the protein level after hormonal withdrawal due to ovariectomy or after estradiol treatment reflect changes at the level of gene transcription...

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[3H]CGP 39653: a new N-methyl-D-aspartate antagonist radioligand with low nanomolar affinity in rat brain

Cited by 208 publications

References 12 publications

Cortical Glutamatergic Markers in Schizophrenia

Cortical Glutamatergic Markers in Schizophrenia

Discovery of a New Class of Ionotropic Glutamate Receptor Antagonists by the Rational Design of (2S,3R)-3-(3-Carboxyphenyl)-pyrrolidine-2-carboxylic Acid

Estrogen-like Activity of Tamoxifen and Raloxifene on NMDA Receptor Binding and Expression of its Subunits in Rat Brain

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