α2C-Adrenoceptor blockade by clozapine and other antipsychotic drugs

Kalkman, Hans O.; Loetscher, Erika

doi:10.1016/s0014-2999(03)01308-6

Cited by 82 publications

(62 citation statements)

References 44 publications

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“…Interactions at 5-HT 7 and 5-HT 2B receptors may be associated with mood benefits and echo the 5-HT 7 and 5-HT 2B interactions of the atypical antipsychotic and D 2 /D 3 receptor antagonist, amisulpride (Abbas et al 2009;Martel et al 2006), which has antidepressant and anti-negative symptoms properties (Moller 2005;Nuss and Tessier 2010). Alpha 2C receptor antagonism is hypothesized to be beneficial for cognitive function in schizophrenia (Kalkman and Loetscher 2003;Marcus et al 2010), although the cardiac safety of alpha 2C blockade may be questioned, in the light of clinical genotyping studies (Bristow et al 2010). Finally, F15063 and adoprazine are partial agonists at D 4 receptors, a property that appears to mediate their capacity to alleviate scopolamine-induced social recognition deficits (Bardin et al 2006b;Depoortere et al 2007a) and would therefore seem desirable for atypical antipsychotics.…”

Section: Introductionmentioning

confidence: 99%

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Newman‐Tancredi

Kleven²

2011

Psychopharmacology

147

108

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Recent compounds exhibiting combined 5-HT(1A)/D(2) properties may be effective in treating a broader range of symptoms of schizophrenia and be better tolerated than existing antipsychotics. Nevertheless, further investigations are necessary to evaluate recent compounds, notably in view of their differing levels of 5-HT(1A) affinity and efficacy, which can markedly influence activity and side-effect profiles.

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Section: Introductionmentioning

confidence: 99%

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Newman‐Tancredi

Kleven²

2011

Psychopharmacology

147

108

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“…It seems clear that defective GABAergic signaling could result in increased glutamatergic transmission that might account for the observed psychosis common to schizophrenia and bipolar disorder (12). The concept of schizophrenia arising from a defect of GABAergic neurons and its impact on additional transmitter receptor systems has been previously discussed (5,(13)(14)(15)(16).…”

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confidence: 99%

Reelin promoter hypermethylation in schizophrenia

Grayson

Jia

Chen

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

509

353

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Reelin mRNA and protein levels are reduced by Ϸ50% in various cortical structures of postmortem brain from patients diagnosed with schizophrenia or bipolar illness with psychosis. In addition, the mRNA encoding the methylating enzyme, DNA methyltransferase 1, is up-regulated in the same neurons that coexpress reelin and glutamic acid decarboxylase 67. We have analyzed the extent and pattern of methylation within the CpG island of the reelin promoter in genomic DNA isolated from cortices of schizophrenia patients and nonpsychiatric subjects. Ten (The Stanley Foundation Neuropathology Consortium) and five (Harvard Brain Collection) schizophrenia patients and an equal number of nonpsychiatric subjects were selected from each brain collection. Genomic DNA was isolated, amplified (from base pair ؊527 to base pair ؉322) after bisulphite treatment, and sequenced. The results show that within the promoter region there were interesting regional variations. There was increased methylation at positions ؊134 and ؊139, which is particularly important for regulation, because this portion of the promoter is functionally competent based on transient transfection assays. This promoter region binds a protein present in neuronal precursor nuclear extracts that express very low levels of reelin mRNA; i.e., an oligonucleotide corresponding to this region and that contains methylated cytosines binds more tightly to extracts from nonexpressing cells than the nonmethylated counterpart. Collectively, the data show that this promoter region has positive and negative properties and that the function of this complex cis element relates to its methylation status.DNA methyltransferase ͉ epigenetics ͉ gene regulation ͉ methylation ͉ psychiatric disorder S chizophrenia is a devastating disorder with a populationwide morbidity approaching 1%. The genetics of the disease are perhaps one of the most studied facets of schizophrenia, but the results of multiple linkage analyses have not provided a clarification of underlying etiological factors that define the symptomatology of the disease (1, 2). However, insight has come from recent reports that examined biological markers that appear to be aberrantly regulated in postmortem brains of patients diagnosed with schizophrenia (3-5). It was noted that among Ͼ100 different markers examined, reelin and glutamic acid decarboxylase (GAD) 67 are the most abnormal in the context of schizophrenia and bipolar illness (6). These two mRNAs and their cognate proteins are selectively coexpressed in GABAergic neurons of the mammalian cortex. The observation that reelin and GAD 67 are down-regulated has been one of the more consistently replicated findings observed in postmortem cortex from schizophrenia patients (SZP). We previously reported reelin mRNA and protein levels are quantitatively reduced by Ϸ50% in various cortical structures of postmortem brain from SZP and bipolar patients (3, 4). The results obtained with respect to reelin were independently confirmed immunohistochemically in the hippocampus (7) and ...

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“…Exploration of the significance of ␣ 2C -AR blockade to the functional profile of S33138 would be of interest because activation of ␣ 2C -ARs in frontal cortex and hippocampus may compromise cognitive performance (Marcus et al, 2005;Soto-Moyano et al, 2005). Moreover, antagonism of corticolimbic and striatal ␣ 2C -ARs may contribute to the atypical profile of clozapine, including its low EPS potential (Millan et al, 2001'02;Kalkman and Loetscher, 2003;Svensson, 2003).…”

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confidence: 99%

S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], A Preferential Dopamine D₃versus D₂Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors

Millan

Cour²,

Novi³

et al. 2007

J Pharmacol Exp Ther

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The novel, potential antipsychotic, S33138 (N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]benzopyrano [3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide), displayed ϳ25-fold higher affinity at human (h) dopamine D 3 versus hD 2L (long isoform) and hD 2S (short isoform) receptors (pK i values, 8.7, 7.1, and 7.3, respectively). Conversely, haloperidol, clozapine, olanzapine, and risperidone displayed similar affinities for hD 3 , hD 2L , and hD 2S sites. In guanosine-5Ј-O-(3-[35 S]thio)-triphosphate ([ 35 S]-GTP␥S) filtration assays, S33138 showed potent, pure, and competitive antagonist properties at hD 3 receptors, displaying pK B and pA 2 values of 8.9 and 8.7, respectively. Higher concentrations were required to block hD 2L and hD 2S receptors. Preferential antagonist properties of S33138 at hD 3 versus hD 2L receptors were underpinned in antibody capture/scintillation proximity assays (SPAs) of G␣ i3 recruitment and in measures of extracellular-regulated kinase phosphorylation. In addition, in cells cotransfected with hD 3 and hD 2L receptors that assemble into heterodimers, S33138 blocked (pK B , 8.5) the inhibitory influence of quinpirole upon forskolin-stimulated cAMP formation. S33138 had low affinity for hD 4 receptors (Ͻ5.0) but revealed weak antagonist activity at hD 1 receptors (G␣s/SPA, pK B , 6.3) and hD 5 sites (adenylyl cyclase, 6.5). Modest antagonist properties were also seen at human serotonin (5-HT) 2A receptors (G␣ q /SPA, pK B , 6.8, and inositol formation, 6.9) and at 5-HT 7 receptors (adenylyl cyclase, pK B , 7.1). In addition, S33138 antagonized h␣ 2C adrenoceptors ([ 35 S]GTP␥S, 7.2; G␣ i3 /SPA, 6.9; G␣ o /SPA, 7.3, and extracellular-regulated-kinase, 7.1) but not h␣ 2A or h␣ 2B adrenoceptors (Ͻ5.0). Finally, in contrast to haloperidol, clozapine, olanzapine, and risperidone, S33138 displayed negligible affinities for multiple subtypes of ␣ 1 -adrenoceptor, muscarinic, and histamine receptor. In conclusion, S33138 possesses a distinctive receptor-binding profile and behaves, in contrast to clinically available antipsychotics, as a preferential antagonist at hD 3 versus hD 2 receptors.Schizophrenia is a complex, progressive, and debilitating disorder of early onset that afflicts approximately 1% of the population. It is characterized by disorganized thought and a constellation of symptoms generally classified as positive (delusions and hallucinations), negative (social withdrawal, blunted affect, and mutism), and cognitive (deficits in attention, working and verbal memory, social cognition, and execArticle, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.107.126706.ABBREVIATIONS: EPS, extrapyramidal motor symptom; AR, adrenoceptor; H 1 , histamine; DA, dopamine;3a,4, R(ϩ)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-

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α2C-Adrenoceptor blockade by clozapine and other antipsychotic drugs

Cited by 82 publications

References 44 publications

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Reelin promoter hypermethylation in schizophrenia

S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], A Preferential Dopamine D₃versus D₂Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors

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α2C-Adrenoceptor blockade by clozapine and other antipsychotic drugs

Cited by 82 publications

References 44 publications

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Comparative pharmacology of antipsychotics possessing combined dopamine D2 and serotonin 5-HT1A receptor properties

Reelin promoter hypermethylation in schizophrenia

S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], A Preferential Dopamine D3versus D2Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors

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S33138 [N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)-ethyl]phenylacetamide], A Preferential Dopamine D₃versus D₂Receptor Antagonist and Potential Antipsychotic Agent: I. Receptor-Binding Profile and Functional Actions at G-Protein-Coupled Receptors