Mapping of Dopamine D<sub>3</sub>Receptor Binding Site by Pharmacological Characterization of Mutants Expressed in Cho Cells with the Semliki Forest Virus System

Lundström, Kenneth; Turpin, Michael P.; Large, Charles H.; Robertson, Graeme M.; Thomas, Paul G.; Lewell, Xiao Qing

doi:10.3109/10799899809047741

Cited by 47 publications

(61 citation statements)

References 20 publications

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“…According to our results, the DRD3 Ser9Gly polymorphism explains approximately 3.1% of the variance in executive functioning (range 2.9-6.2%), a result similar to that reported for the Val158Met by other authors [Egan et al, 2001]. Interestingly, our results suggest better cognitive performance associated with a higher proportion of the Ser9 allele, which has been associated with lower dopaminergic binding [Lundstrom and Turpin, 1996;Lundstrom et al, 1998]. However, the relationship between cognitive functioning and dopamine activity does not seem to follow a simple linear relationship, but rather an inverted U-shaped one [GoldmanRakic, 1998;Tunbridge et al, 2006a].…”

Section: Discussionsupporting

confidence: 78%

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DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first‐episode psychosis adolescents

Bombín

Arango

Mayoral

et al. 2008

American J of Med Genetics Pt B

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Catechol-O-methyltransferase (COMT) and dopamine receptors 2 (DRD2) and 3 (DRD3) have been associated with a higher risk of developing psychosis and with dopaminergic system (DAS) regulation. Frontal cognitive functioning has been proven to be a useful endophenotype for psychosis and it is partially controlled by the DAS. Val158Met (rs4680, COMT), Taq IA (rs1800497, DRD2) and Ser9Gly (rs6280; DRD3) polymorphisms were analyzed in a sample of 84 adolescent Caucasian patients with first-episode psychosis (ages 11-17) and 85 healthy Caucasian controls (ages 10-17). A comprehensive neuropsychological battery, assessing attention, working memory, memory, and executive functions, was administered to the entire sample. The relationship between neuropsychological scores and genotype was determined. Subjects with the DRD3 Gly/Gly genotype showed significantly poorer performance than Ser/Ser subjects in executive functioning tasks (P = 0.002; adjusted R(2) = 0.031), with no significant differences in the other cognitive paradigms. Neither COMT nor DRD2 polymorphisms significantly contributed to variance in cognition in our adolescent sample. The DRD3 Ser9Gly polymorphism seems to be involved with prefrontal cognition. This effect seems to be heterogeneous in terms of cognitive paradigms. The lack of association between COMT and DRD2 genotypes and cognition in our sample may be partially explained by the young age of the sample and the clinical heterogeneity of the patients.

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Section: Discussionsupporting

confidence: 78%

“…According to Hall et al [1996], increased DRD3 densities occur in the basal ganglia, but the cerebellum also expresses DRD3 at a lower level. Functional studies have reported an increased rate of dopamine binding affinity of the Gly/Gly homozygote compared to the other two variants [Lundstrom and Turpin, 1996;Lundstrom et al, 1998]. …”

Section: Introductionmentioning

confidence: 99%

DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first‐episode psychosis adolescents

Bombín

Arango

Mayoral

et al. 2008

American J of Med Genetics Pt B

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“…Moreover, functional differences between the two alleles (or genotypes ) have not yet been clearly demonstrated. 4 The DRD3 gene locus, 3q13.3, is not a region where significant linkage has been reported in schizophrenia. However, these findings raise the possibility that the Ser9Gly variant is in linkage disequilibrium (LD) with one or more susceptibility variants elsewhere in the gene.…”

Section: Introductionmentioning

confidence: 99%

Characterisation, mutation detection, and association analysis of alternative promoters and 5′ UTRs of the human dopamine D3 receptor gene in schizophrenia

et al. 2002

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The dopamine D 3 receptor gene (DRD3) is a candidate for a number of psychiatric conditions including schizophrenia, bipolar disorder and alcohol and drug abuse. Previous studies have reported associations between polymorphisms in DRD3 and these disorders, but these findings may have reflected linkage disequilibrium with pathogenic variants that are further upstream. We have isolated and sequenced approximately 9 kb of genomic sequence upstream of the human DRD3 translational start site. Using 5Ј RACE, we have identified within this region three additional exons and two putative promoter regions which show promoter activity in three different cell lines. A 5Ј UTR identified only in lymphoblasts is spread over three exons and is 353 bp long. A second 5Ј UTR, found in adult and fetal brain, lymphocytes, kidney and placenta is spread over two exons and is 516 bp long. A 260-bp sequence within this 9 kb corresponds to a previously reported EST, but corresponding mRNA could not be found in the tissues above. The EST, 5Ј UTRs and putative promoter regions have been analysed for polymorphisms, revealing 10 single nucleotide polymorphisms, seven of which were tested for association in a large sample of unrelated patients with schizophrenia and matched controls. No associations were observed with schizophrenia. In addition we failed to replicate previous findings of association with homozygosity of the Ser9Gly variant. The results from this study imply that neither the coding nor the regulatory region of DRD3 plays a major role in predisposition to schizophrenia.

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“…[10] Furthermore, mutagenesis data corroborate that position 6.55 is involved in altering agonist/antagonist binding affinity. [11,12] Table 1 lists experimentally measured binding affinities of clozapine and olanzapine for the receptors studied. [13,14] A close inspection of these affinity values shows that they are significantly higher for the receptors with a serine residue at position 3.36 than those with cysteine at the same position (Student t test, p < 0.001), as shown in Figure 3.…”

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confidence: 99%

Multi‐Receptor Binding Profile of Clozapine and Olanzapine: A Structural Study Based on the New β₂ Adrenergic Receptor Template

et al. 2008

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Schizophrenia is a devastating mental disorder that has a large impact on the quality of life for those who are afflicted and is very costly for families and society.[1] Although the etiology of schizophrenia is still unknown and no cure has yet been found, it is treatable, and pharmacological therapy often produces satisfactory results. Among the various antipsychotic drugs in use, clozapine is widely recognized as one of the most clinically effective agents, even if it elicits significant side effects such as metabolic disorders and agranulocytosis. Clozapine and the closely related compound olanzapine are good examples of drugs with a complex multi-receptor profile; [2] they have affinities toward serotonin, dopamine, a adrenergic, muscarinic, and histamine receptors, among others.Experimental evidence suggests that a complex binding profile is linked to the clinical efficacy of antipsychotic drugs, and indeed, some of the latest efforts in the development of novel antipsychotic drugs [3] are aimed at obtaining compounds with clozapine-like binding affinities for a certain number of receptors: D 2 , D 3 , 5-HT 2A , 5-HT 2C , 5-HT 6 . Unfortunately, our current understanding of which receptors are relevant for the clinical efficacy of antipsychotic agents is based only on the study of a handful of drugs. At this stage, a clear discrimination between clinically useful receptors and those responsible for adverse effects is not possible, as this would require a more thorough understanding of subtle modulating effects, and this is still obscure. Even if the ideal multi-receptor binding profile was known, the problem of how to obtain ligands with such binding specificity would still remain open. A good starting point is to improve our understanding of the structural features associated with binding profiles, thus leading to clinically useful drugs.In this work, we made use of the recently reported structure of the human b 2 adrenergic receptor as a template to build models for a set of receptors that are putatively important for the pharmacological properties of antipsychotic drugs. The aim of this study is to identify characteristics of the complexes of such receptors with clozapine and olanzapine that can explain the excellent clinical behavior of these two drugs. Remarkably, docking studies with homology models based on the new template reveal a binding complex that is different from previously reported complexes for clozapine-like ligands. [4,5] In the first step, we studied the binding affinities of both olanzapine and clozapine for all the receptors in order to identify their common binding profile and the structural features associated with this profile. We then studied the structural differences between the drug-receptor complexes for both antipsychotic drugs that could be responsible for the observed differences in their pharmacological behavior.For this, structural models for a set of 14 receptors that are potentially involved in the pharmacological profile of antipsychotic drugs (Table 1) were generated b...

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Mapping of Dopamine D₃Receptor Binding Site by Pharmacological Characterization of Mutants Expressed in Cho Cells with the Semliki Forest Virus System

Cited by 47 publications

References 20 publications

DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first‐episode psychosis adolescents

DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first‐episode psychosis adolescents

Characterisation, mutation detection, and association analysis of alternative promoters and 5′ UTRs of the human dopamine D3 receptor gene in schizophrenia

Multi‐Receptor Binding Profile of Clozapine and Olanzapine: A Structural Study Based on the New β₂ Adrenergic Receptor Template

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Mapping of Dopamine D3Receptor Binding Site by Pharmacological Characterization of Mutants Expressed in Cho Cells with the Semliki Forest Virus System

Cited by 47 publications

References 20 publications

DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first‐episode psychosis adolescents

DRD3, but not COMT or DRD2, genotype affects executive functions in healthy and first‐episode psychosis adolescents

Characterisation, mutation detection, and association analysis of alternative promoters and 5′ UTRs of the human dopamine D3 receptor gene in schizophrenia

Multi‐Receptor Binding Profile of Clozapine and Olanzapine: A Structural Study Based on the New β2 Adrenergic Receptor Template

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Mapping of Dopamine D₃Receptor Binding Site by Pharmacological Characterization of Mutants Expressed in Cho Cells with the Semliki Forest Virus System

Multi‐Receptor Binding Profile of Clozapine and Olanzapine: A Structural Study Based on the New β₂ Adrenergic Receptor Template