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Josee E Leysen - One of the best experts on this subject based on the ideXlab platform.
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Influence of the antipsychotic drug Pipamperone on the expression of the dopamine D4 receptor.
Life Sciences, 2006Co-Authors: Kathleen Van Craenenbroeck, Josee E Leysen, Evelien Gellynck, Béatrice Lintermans, Hubert H. M. Van Tol, Guy Haegeman, Peter VanhoenackerAbstract:Abstract The dopamine D4 receptor is a G protein-coupled receptor that binds with high affinity various antipsychotics. The receptor may be involved in attention/cognition, and in genetic studies a polymorphic repeat sequence in its coding sequence has been associated with attention deficit/hyperactivity disorder. We developed an inducible episomal expression system based on the reverse tetracycline transactivator and Epstein-Barr viral sequences. In HEK293rtTA cells expressing the dopamine D4 receptor from this episomal expression vector, addition of doxycycline in combination with sodium butyrate and trichostatin A induces high levels of receptor expression, resulting in 1970 ± 20 fmol/mg membrane protein. Addition of the dopamine D4 receptor and serotonin 5-HT2A receptor antagonist Pipamperone to these cells further increased the expression of the dopamine receptor, reaching 3800 ± 60 fmol/mg membrane protein. This up-regulation was not restricted to the dopamine D4 receptor but was also found for the serotonin 5-HT2A receptor. We further provide evidence that the increase in receptor expression is not due to increased mRNA synthesis. As Pipamperone could rescue the expression of a folding mutant of the dopamine D4 receptor (M345), we propose that Pipamperone acts as a pharmacological chaperone for correct receptor folding thereby resulting in an increased dopamine D4 receptor expression. This study describes a strong and inducible expression system for proteins, difficult to express in other heterologous expression systems. This study also demonstrates that Pipamperone, an antipsychotic, acts as a pharmacological chaperone and by doing so, increases the expression level of the dopamine D4 receptor. The fact that ligands can also act as pharmacological chaperones is a fairly new additional element in the regulation of receptor expression levels with potential great impact in drug treatment.
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Role of 5-HT2 receptors in the tryptamine-induced 5-HT syndrome in rats
Behavioural Pharmacology, 2002Co-Authors: D. Van Oekelen, Anton A. H. P. Megens, Theo F. Meert, Walter Luyten, Josee E LeysenAbstract:We distinguished the functions of the different 5-hydroxytryptamine-2 (5-HT 2 ) receptor (5-HT 2 R) subtypes in the tryptamine-induced 5-HT syndrome in rats using (1) the 5-HT 2 A R antagonist R93274 (N-[(3-p-fluorophenyl-1-propyl)-4-methyl-4-piperidinyl]-4-amino-5-iodo-2-methoxybenzamide), the 5-HT 2 A / C R antagonist R99647 (2-(dimethylaminomethyl)2,3,3a,8-tetrahydrodibenzo[c,f]isoxazolo[2,3-a]azepine), the 5-HT 2 B / C R antagonist SB-242084 (6-chloro-5-methyl-1-[[2-[(2-methyl-3-pyridyl)oxy]-5-pyridyl]carbamoyl]-indoline), and several 5-HT 2 R antagonists (ketanserin, risperidone, Pipamperone and mianserin); and (2) chronic 5-HT 2 R activation by 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM). In contrast to SB-242084, the selective 5-HT 2 A R antagonist R93274 as well as the non-selective 5-HT 2 A R antagonists (R99647, ketanserin, risperidone, Pipamperone and mianserin) significantly inhibited tryptamine-induced forepaw treading and tremors, and reversed peripherally mediated cyanosis into hyperaemia; only the 5-HT 2 A / C R antagonists R99647 and mianserin inhibited the tryptamine-induced hunched back. Intermittent DOM administration (intravenously every 48 h for 12 days) did not change the centrally mediated tryptamine-induced forepaw treading, tremors and hunched back at 1, 4 or 7 days after the last DOM pretreatment. The DOM-induced head twitch response, measured immediately after every DOM injection, was not affected. In contrast, peripherally mediated cyanosis was reversed into hyperaemia in 75, 11 and 20% of all pretreated rats at 1, 4 and 7 days, respectively, after the last DOM administration. Taken together, these finding suggest that central 5-HT 2 A Rs mediate tryptamine-induced forepaw treading and tremors, that peripheral 5-HT 2 A Rs mediate tryptamine-induced cyanosis, and that 5-HT 2 C Rs mediate tryptamine-induced hunched back. Peripheral 5-HT 2 A Rs are more sensitive to desensitization after intermittent treatment with an agonist than central 5-HT 2 A Rs.
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Different regulation of rat 5-HT2A and rat 5-HT2C receptors in NIH 3T3 cells upon exposure to 5-HT and Pipamperone
European Journal of Pharmacology, 2001Co-Authors: Dirk Van Oekelen, Danielle Van De Wiel, Mirek Jurzak, Walter Luyten, Geert Van Hecke, Josee E LeysenAbstract:Abstract The 5-HT 2A and 5-HT 2C receptors belong to the same subtype of the G-protein coupled receptor family and have several agonist and antagonist ligands in common. To gain more insight into the differences in the regulation of the two receptors, we studied the effect of agonist and antagonist pre-treatment on radioligand receptor binding and 5-HT-induced inositol phosphate formation on rat 5-HT 2A and rat 5-HT 2C receptors stable expressed in NIH 3T3 cells. We compared short (15 min) and prolonged (48 h) pre-treatment of the cells with the natural agonist, 5-HT and with the antagonist Pipamperone, which can be readily washed out. The rat 5-HT 2C receptor showed an agonist-induced down-regulation (decrease in B max of labelled agonist and antagonist binding) and desensitisation (decrease in 5-HT-induced inositol phosphate formation and potency of 5-HT). Antagonist pre-treatment induced an increase in rat 5-HT 2C receptor-mediated inositol phosphate formation as well as increased agonist and antagonist radioligand binding. These findings are consistent with the classical model of G-protein coupled receptor regulation. In contrast, the rat 5-HT 2A receptor expressed in the same host cell behaved differently, unlike the classical model. Pre-treatment with 5-HT for 15 min and 48 h did not change receptor levels measured by radioligand binding, but the signal transduction response (inositol phosphate formation) was significantly reduced. Pre-treatment with the antagonist Pipamperone for 15 min and 48 h caused an increase in antagonist radioligand binding but a reduction in agonist radioligand binding and a decrease in inositol phosphate formation and potency of 5-HT. Hence, the rat 5-HT 2A receptor apparently undergoes agonist desensitisation without down-regulation of the total receptor number. Antagonist pre-treatment causes a paradoxical desensitisation, possibly by uncoupling of the receptor from G-proteins. The uncoupled receptor does not bind 5-HT in the nanomolar range but retains its antagonist binding properties. Paradoxical antagonist-induced desensitisation of rat 5-HT 2A receptors has also been observed in vivo.
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Effects of recent and reference antipsychotic agents at human dopamine D2 and D3 receptor signaling in Chinese hamster ovary cells.
Psychopharmacology, 2000Co-Authors: Jurgen F.m. Vanhauwe, Martine Ercken, Danielle Van De Wiel, Mirek Jurzak, Josee E LeysenAbstract:Rationale: Central dopamine D2 receptor blockade is an essential property of antipsychotic agents in the treatment of schizophrenia. However, for certain of the newer antipsychotics (e.g., sertindole), the in vitro D2 receptor binding affinity does not correlate with in vivo central dopamine antagonism. Objective: This study aimed to investigate the effect and potency of haloperidol, Pipamperone, clozapine, risperidone, sertindole, zotepine, olanzapine, and quetiapine on signaling pathways of human dopamine D2S and D3 receptors expressed in Chinese hamster ovary cells and to relate this to their dopamine antagonist potency in vivo. Methods: Chinese hamster ovary cells, stably expressing high levels of hD2S and hD3 receptors were cultured; dopamine-stimulated [35S]-GTPγS binding was investigated in cell membrane preparations, and forskolin-induced cAMP formation was measured in intact cells. Results: The antipsychotic agents inhibited dopamine-stimulated [35S]-GTPγS binding mediated by hD2S and hD3 receptors with potencies equal to their receptor binding affinities. The antipsychotics reversed dopamine inhibition of cAMP formation (equally well detectable with both hD2S and hD3 receptors) dose dependently at both receptors. Partial agonist effects were not observed with any of the antipsychotics. Antagonistic potencies of haloperidol, risperidone, and Pipamperone in the cAMP test were equal to their receptor binding affinities. Sertindole and olanzapine were more than ten times less potent dopamine antagonists in the intact cell assay than in the assay using cell membranes; the other compounds showed less marked potency differences. Conclusions: Olanzapine and sertindole were less efficacious dopamine antagonists in intact cell assays, possibly due to avid uptake in cells. For sertindole, the weak hD2S receptor antagonism in intact cells corresponded to a weak in vivo central dopamine antagonism assessed in rats. However, for olanzapine, hD2S receptor binding affinity correlated better with its in vivo dopamine antagonist potency. Such discrepancies may be further explained by relative differences of the compounds in penetrating into the brain.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding.
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. H. M. L. Luyten, PAUL GOMPEL, A. S. Lesage, K. Loore, W Gommeren, Josee E LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, Pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so Pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, Pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
Willy E. Lambert - One of the best experts on this subject based on the ideXlab platform.
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The use of dried blood spots for quantification of 15 antipsychotics and 7 metabolites with ultra-high performance liquid chromatography-tandem mass spectrometry
Drug Testing and Analysis, 2014Co-Authors: Lisbeth Patteet, Christophe P. Stove, Willy E. Lambert, Kristof E. Maudens, Manuel Morrens, Bernard Sabbe, Hugo NeelsAbstract:Therapeutic drug monitoring of antipsychotics is important in optimizing individual therapy. In psychiatric populations, classical venous blood sampling is experienced as frightening. Interest in alternative techniques, like dried blood spots (DBS), has consequently increased. A fast and easy to perform DBS method for quantification of 16 antipsychotics (amisulpride, aripiprazole, asenapine, bromperidol, clozapine, haloperidol, iloperidone, levosulpiride, lurasidone, olanzapine, paliperidone, Pipamperone, quetiapine, risperidone, sertindole and zuclopenthixol) and 8 metabolites was developed. DBS were prepared using 25 μL of whole blood and extraction of complete spots was performed using methanol: methyl-t-butyl-ether (4:1). After evaporation, the extract was reconstituted in the mobile phase and 10 μL were injected on an ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Separation using a C18 column and gradient elution with a flow rate of 0.5 mL/min resulted in a 6-min run-time. Ionization was performed in positive mode and a dynamic MRM method was applied. Median recovery was 66.4 % (range 28.7-84.5%). Accuracy was within the acceptance criteria, except for Pipamperone (LLOQ and low concentration) and lurasidone (low concentration). Imprecision was only aberrant for lurasidone at low and medium concentration. All compounds were stable during 1 month at room temperature, 4 °C and −18 °C. Lurasidone was unstable when the extract was stored for 12 h on the autosampler. Absolute matrix effects (ME) (median 66.1%) were compensated by the use of deuterated IS (median 98.8%). The DBS method was successfully applied on 25-μL capillary DBS from patients and proved to be a reliable alternative for quantification of all antipsychotics except for olanzapine and N-desmethylolanzapine. Copyright © 2014 John Wiley & Sons, Ltd.
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Determination of four basic pharmaceuticals and one pesticide in surface water with UPLC-ESI-MS/MS
International Journal of Environmental Analytical Chemistry, 2011Co-Authors: Jet C. Van De Steene, Willy E. LambertAbstract:This paper describes the optimisation and validation of an ultra performance liquid chromatography- tandem mass spectrometry (UPLC-MS/MS) method for the analysis of four pharmaceuticals (flubendazole, Pipamperone, rabeprazole and domperidone) and one pesticide (propiconazole) in surface water. Sample preparation was reduced substantially as compared to a previously published high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, thanks to the use of UPLC. In addition, internal standards could now be used for quantification instead of the standard addition method. Extraction was performed on a Speedisk phenyl solid-phase extraction tube. A Waters Acquity HSS T3 UPLC column (100 × 2.1 mm i.d.; 1.8-µm particles) was used for separation and an API 4000 triple quadrupole was used as a detector. Total run time was 8.59 minutes. Matrix effects were examined on different surface water samples. Limits of detection and quantification in surface water samples were between 100 and 500 pg/l...
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A field study on 8 pharmaceuticals and 1 pesticide in Belgium: removal rates in waste water treatment plants and occurrence in surface water.
Science of The Total Environment, 2010Co-Authors: Jet C. Van De Steene, Christophe P. Stove, Willy E. LambertAbstract:Abstract Only recently, attention has been drawn towards the occurrence of pharmaceuticals in the environment. In recent years many reports have been made on the occurrence of the large, differentiated group of pharmaceuticals in waste water, surface water, ground water and in soil. In this study, we demonstrate the applicability of a previously developed LC-MS/MS method by evaluating in waste water and surface water samples from Belgium the occurrence of 8 pharmaceuticals and 1 pesticide (flubendazole, Pipamperone, rabeprazole, domperidone, ketoconazole, itraconazole, cinnarizine, miconazole and propiconazole). Removal rates in five public waste water treatment plants were assessed. Introduction of several compounds into the aquatic environment by discharge of effluent could be demonstrated. For several compounds, the highest concentrations (up to 35.6 μg/l for Pipamperone) were observed in the effluent of a WWTP receiving water from chemo-pharmaceutical and other industrial companies. The occurrence of these compounds in the aquatic environment was assessed by analyzing 16 surface water samples, taken from various locations. Four pharmaceuticals (flubendazole, Pipamperone, domperidone and cinnarizine) could be detected in at least one sample at low concentrations (up to 26.4 ng/l). The pesticide propiconazole was found in comparable concentrations (up to 85.9 ng/l) as in effluent, suggesting potential introduction by direct seepage of water from rural grounds. The highest concentrations of flubendazole, Pipamperone, domperidone, propiconazole and cinnarizine (up to 961.3 ng/l) were observed in a sample, taken near the discharge of a WWTP receiving water from chemo-pharmaceutical and other industries. An initial environmental risk assessment was done based on these results.
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Validation of a solid-phase extraction and liquid chromatography-electrospray tandem mass spectrometric method for the determination of nine basic pharmaceuticals in wastewater and surface water samples.
Journal of Chromatography A, 2008Co-Authors: Jet C. Van De Steene, Willy E. LambertAbstract:Abstract This paper reports the development and validation of a quantitative LC–electrospray (ESI)-MS/MS method for the simultaneous analysis of nine basic pharmaceuticals (flubendazole, Pipamperone, cinnarizine, ketoconazole, miconazole, rabeprazole, itraconazole, domperidone and propiconazole) in environmental waters. Sample preparation consisted of solid-phase extraction on a Speedisk phenyl and a NH 2 solid-phase extraction tube for sample clean-up. Chromatography was performed on a pentafluorophenyl column in a total run time of 24 min. Due to different matrix effects measured in different surface water samples, standard addition was the only method to perform accurate quantification. Limits of detection and quantification were in the range of
F. Safta - One of the best experts on this subject based on the ideXlab platform.
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stability indicating lc method for the determination of Pipamperone
Journal of Pharmaceutical and Biomedical Analysis, 2005Co-Authors: H. Trabelsi, I.e. Hassen, S. Bouabdallah, K. Bouzouita, F. SaftaAbstract:A high performance liquid chromatographic method for the determination of Pipamperone in the presence of one related impurity and its degradation products is described. The method is based on the use of an amide functionalized bonded phase column (LC-ABZ+ Plus) and a mobile phase of acetonitrile-tetrahydrofuran-sodium phosphate monobasic (0.05 M, pH 6.5) (16:11:73, v/v/v). All peaks are eluted in <8 min. The method was demonstrated to be precise, accurate and specific. Degradation study showed that the drug is stable in acidic medium while it degrades under basic and oxidative conditions. The results indicated that the proposed method could be used in a stability assay.
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Stability indicating LC method for the determination of Pipamperone.
Journal of Pharmaceutical and Biomedical Analysis, 2005Co-Authors: H. Trabelsi, I.e. Hassen, S. Bouabdallah, K. Bouzouita, F. SaftaAbstract:A high performance liquid chromatographic method for the determination of Pipamperone in the presence of one related impurity and its degradation products is described. The method is based on the use of an amide functionalized bonded phase column (LC-ABZ+ Plus) and a mobile phase of acetonitrile-tetrahydrofuran-sodium phosphate monobasic (0.05 M, pH 6.5) (16:11:73, v/v/v). All peaks are eluted in
A. Schotte - One of the best experts on this subject based on the ideXlab platform.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding.
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. H. M. L. Luyten, PAUL GOMPEL, A. S. Lesage, K. Loore, W Gommeren, Josee E LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, Pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so Pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, Pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. H. M. L. Luyten, PAUL GOMPEL, A. S. Lesage, K. Loore, W Gommeren, Josee E LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, Pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT_2A receptors and D_2-type receptors. Predominant 5HT_2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D_2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D_3 and in particular D_4 receptors has been proposed. In vitro, all compounds, except the ‘typical’ antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT_2A than for D_2 receptors. Subnanomolar affinity for human 5HT_2A receptors was observed for ORG-5222, sertindole, resperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D_2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D_2 affinity in vitro. Clozapine, but even more so Pipamperone, displayed higher affinity for D_4 than for D_2 receptors. For most other compounds, D_4 affinity was only slightly lower than their D_2 affinity. Seroquel was totally devoid of D_4 affinity. None of the compounds had nanomolar affinity for D_1 receptors; their affinity for D_3 receptors was usually slightly lower than for D_2 receptors. In vivo, ORG-5222, risperidone, Pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT_2A than D_2 receptors. Risperidone and ORG-5222 had 5HT_2A versus D_2 potency ratio of about 20. Highest potency for 5HT_2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT_2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D_2 receptors. No regional selectivity for D_2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D_2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic α_1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more α_1 than D_2 receptors. Clozapine showed predominant occupancy of H_1 receptors and occupied cholinergic receptors with equivalent potency to D_2 receptors. A stronger predominance of 5HT_2A versus D_2 receptor occupancy combined with a more gradual occupancy of D_2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT_2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D_2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT_2A and D_2 occupancy and the avoidance of D_2 receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. H. M. L. Luyten, PAUL GOMPEL, A. S. Lesage, K. Loore, W Gommeren, Josee E LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, Pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed.
W Gommeren - One of the best experts on this subject based on the ideXlab platform.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding.
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. H. M. L. Luyten, PAUL GOMPEL, A. S. Lesage, K. Loore, W Gommeren, Josee E LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, Pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed. In vitro, all compounds, except the 'typical' antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT2A than for D2 receptors. Subnanomolar affinity for human 5HT2A receptors was observed for ORG-5222, sertindole, risperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D2 affinity in vitro. Clozapine, but even more so Pipamperone, displayed higher affinity for D4 than for D2 receptors. For most other compounds, D4 affinity was only slightly lower than their D2 affinity. Seroquel was totally devoid of D4 affinity. None of the compounds had nanomolar affinity for D1 receptors; their affinity for D3 receptors was usually slightly lower than for D2 receptors. In vivo, ORG-5222, risperidone, Pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT2A than D2 receptors. Risperidone and ORG-5222 had 5HT2A versus D2 potency ratio of about 20. Highest potency for 5HT2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D2 receptors. No regional selectivity for D2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic alpha 1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more alpha 1 than D2 receptors. Clozapine showed predominant occupancy of H1 receptors and occupied cholinergic receptors with equivalent potency to D2 receptors. A stronger predominance of 5HT2A versus D2 receptor occupancy combined with a more gradual occupancy of D2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT2A and D2 occupancy and the avoidance of D2 receptor overblockade are believed to reduce the risk for extrapyra
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. H. M. L. Luyten, PAUL GOMPEL, A. S. Lesage, K. Loore, W Gommeren, Josee E LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, Pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT_2A receptors and D_2-type receptors. Predominant 5HT_2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D_2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D_3 and in particular D_4 receptors has been proposed. In vitro, all compounds, except the ‘typical’ antipsychotics haloperidol and fluspirilene, showed higher affinity for 5HT_2A than for D_2 receptors. Subnanomolar affinity for human 5HT_2A receptors was observed for ORG-5222, sertindole, resperidone, 9-OH-risperidone and ziprasidone. Fluspirilene, ORG-5222, haloperidol, ziprasidone, risperidone, 9-OH-risperidone and zotepine displayed nanomolar affinity for human D_2 receptors. Sertindole and olanzapine were slightly less potent. Pipamperone, clozapine and seroquel showed 2 orders of magnitude lower D_2 affinity in vitro. Clozapine, but even more so Pipamperone, displayed higher affinity for D_4 than for D_2 receptors. For most other compounds, D_4 affinity was only slightly lower than their D_2 affinity. Seroquel was totally devoid of D_4 affinity. None of the compounds had nanomolar affinity for D_1 receptors; their affinity for D_3 receptors was usually slightly lower than for D_2 receptors. In vivo, ORG-5222, risperidone, Pipamperone, 9-OH-risperidone, sertindole, olanzapine, zotepine and clozapine maintained a higher potency for occupying 5HT_2A than D_2 receptors. Risperidone and ORG-5222 had 5HT_2A versus D_2 potency ratio of about 20. Highest potency for 5HT_2A receptor occupancy was observed for ORG-5222 followed by risperidone and olanzapine. Ziprasidone exclusively occupied 5HT_2A receptors. ORG-5222, haloperidol, fluspirilene and olanzapine showed the highest potency for occupying D_2 receptors. No regional selectivity for D_2 receptor occupancy in mesolimbic versus nigrostriatal areas was detected for any of the test compounds. Risperidone was conspicuous because of its more gradual occupancy of D_2 receptors; none of the other compounds showed this property. The various compounds also displayed high to moderate occupancy of adrenergic α_1 receptors, except fluspirilene and ziprasidone. Clozapine, zotepine, ORG-5222 and sertindole occupied even more α_1 than D_2 receptors. Clozapine showed predominant occupancy of H_1 receptors and occupied cholinergic receptors with equivalent potency to D_2 receptors. A stronger predominance of 5HT_2A versus D_2 receptor occupancy combined with a more gradual occupancy of D_2 receptors differentiates risperidone and its 9-OH-metabolite from the other antipsychotic compounds in this study. The predominant 5HT_2A receptor occupancy probably plays a role in the beneficial action of risperidone on the negative symptoms of schizophrenia, whereas maintenance of a moderate occupancy of D_2 receptors seems adequate for treating the positive symptoms of schizophrenia. A combined 5HT_2A and D_2 occupancy and the avoidance of D_2 receptor overblockade are believed to reduce the risk for extrapyramidal symptoms.
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Risperidone compared with new and reference antipsychotic drugs: in vitro and in vivo receptor binding
Psychopharmacology, 1996Co-Authors: A. Schotte, P. F. M. Janssen, W. H. M. L. Luyten, PAUL GOMPEL, A. S. Lesage, K. Loore, W Gommeren, Josee E LeysenAbstract:Risperidone and its active metabolite 9-OH-risperidone were compared to reference antipsychotic drugs (haloperidol, Pipamperone, fluspirilene, clozapine, zotepine) and compounds under development (olanzapine, seroquel, sertindole, ORG-5222, ziprasidone) for in vitro binding to neurotransmitter receptors in brain tissue and on membranes of recombinant cells expressing cloned human receptors and for in vivo occupancy of neurotransmitter receptors in rat and guinea-pig brain following acute treatment (2 h., s.c.). An ex vivo autoradiography technique was applied to determine the receptor occupancy by the drugs administered in vivo. Of particular interest are the central 5HT2A receptors and D2-type receptors. Predominant 5HT2A receptor antagonism is supposed to add to an atypical profile of the antipsychotics (treatment of the negative symptoms, low incidence of extrapyramidal side effects). D2 antagonism is required for the treatment of positive symptoms. A contribution of the new dopamine receptor subtypes D3 and in particular D4 receptors has been proposed.