Binding characteristics of remoxipride and its metabolites to dopamine D2 and D3 receptors

Mohell, Nina; Sällemark, Maria; Rosqvist, Susanne; Malmberg, Åsa; Högberg, Thomas; Jackson, David M.

doi:10.1016/0014-2999(93)90515-j

Cited by 46 publications

(19 citation statements)

References 15 publications

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“…Thus, clozapine exhibits moderate to high affinities at muscarinic, Db D2, D3, D4, 5-HT2c, and oq receptors (Canton et al 1990;Bolden et al 1991;Van Tol et al 1991;Shaik et al 1993). Haloperidol has moderate to high affinity for D2, 5-HT2 and cq receptors, in contrast to raclopride and remoxipride which are highly selective D2/D3 receptor ligands Mohell et al Malmberg 1993;. Furthermore, several potentially psychoactive metabolites of these compounds have been identified.…”

Section: Discussionmentioning

confidence: 98%

The atypical antipsychotic, remoxipride, blocks phencyclidine-induced disruption of prepulse inhibition in the rat

1994

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The effect of various typical (haloperidol) and atypical (clozapine, raclopride, remoxipride) antipsychotics on phencyclidine (PCP)-induced disruption of sensorimotor gating was tested in rats using an acoustic startle paradigm. Clozapine (4-40 mumol/kg), haloperidol (1-5 mumol/kg) and raclopride (1-12 mumol/kg) failed to reverse PCP-induced disruption of prepulse inhibition (PPI) of the acoustic startle response. In contrast, remoxipride (12-60 mumol/kg) caused a dose-dependent block of this effect. PCP-induced disruption of PPI is a widely accepted animal model of a corresponding behavioural deficit observed in schizophrenia although little evidence has been presented that it is in fact sensitive to antipsychotic agents. The present results indicate that remoxipride behaves in a unique way in this model compared to clozapine, haloperidol and raclopride.

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Section: Discussionmentioning

confidence: 98%

The atypical antipsychotic, remoxipride, blocks phencyclidine-induced disruption of prepulse inhibition in the rat

1994

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“…Unfortunately, typical antipsychotics such as haloperidol are accompanied by a high incidence of extrapyramidal side e¤ects. Atypical antipsychotics, on the other hand, show a low incidence of extrapyramidal side e¤ects, but can at present not be di¤erentiated from typical antipsychotics on the basis of their receptor a¦nities either for dopaminergic or non-dopaminergic receptors Mohell et al 1993). However, it is still possible that the unique therapeutic properties of these drugs are related to actions at receptors less a¤ected by typical antipsychotics.…”

Section: Introductionmentioning

confidence: 98%

(−)Alprenolol potentiates the disrupting effects of dizocilpine on sensorimotor function in the rat

Zhang

Engel

Jackson³

et al. 1997

Psychopharmacology

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The beta-adrenoceptor antagonist as well as serotonin 5-HT1 receptor antagonist, (-)alprenolol, was found to potentiate the disrupting effect of the noncompetitive NMDA receptor antagonist, dizocilpine, on prepulse inhibition (PPI) of the acoustic startle response (ASR) in the rat. The facilitating effect of dizocilpine on ASR amplitude was also potentiated by (-)alprenolol. (-)Alprenolol by itself did not affect either of these measures. These effects did not seem to be related to the unselective beta-adrenoceptor antagonist property of (-)alprenolol, since combined pretreatment with the beta1- and beta2-adrenoceptor antagonists, metoprolol and ICI 118551, did not alter the effects of dizocilpine on startle behaviour. However, a serotonergic influence was suggested by the fact that a facilitating effect of dizocilpine on ASR amplitude was also obtained by pretreatment with the 5-HT precursor, L-5-HTP, in benserazide-pretreated rats. Furthermore, pretreatment with the 5-HT2 selective receptor antagonist, MDL 100907, significantly reduced the (-)alprenolol-induced potentiation of the effects of dizocilpine on startle behaviour, while the 5-HT3 selective receptor antagonist, ondansetron, failed to do that. Finally, the (-)alprenolol-induced potentiation of the effects of dizocilpine was significantly reduced by pretreatment with the atypical antipsychotic, clozapine, and by the potential antipsychotic and selective dopamine D2 receptor antagonist, raclopride. This study suggests that altered 5-HT activity may influence the effects of psychotomimetic drugs such as dizocilpine on sensorimotor function, and this observation may have implications for the pharmacological treatment of schizophrenia in humans.

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“…Finally, the estimated EC 50,rem,prl of 64 nM was 2-4-fold different from in vitro binding potencies of 113 nM (33) and 240 nM (34) for remoxipride on striatal D2 receptors measured in rat brain homogenate, but comparable to the EC 50 of 80 nM found for the previously developed pool model on basis of in vivo data (9). The discrepancy between in vivo and in vitro estimates might be explained by a role of active metabolites (25).…”

Section: Pk/pd Model For Prlmentioning

confidence: 61%

“…The discrepancy between in vivo and in vitro estimates might be explained by a role of active metabolites (25). Although their concentrations in plasma are 10-1000 times lower compared to remoxipride (25), four metabolites (FLA797, FLA908, NCQ436, NCQ469) showed 2-200 times higher in vitro affinity for the D2 receptor than the parent remoxipride (33). Moreover, these metabolites showed in vivo activity on DOPA accumulation in rat striatum (35).…”

Section: Pk/pd Model For Prlmentioning

confidence: 99%

Revealing the Neuroendocrine Response After Remoxipride Treatment Using Multi-Biomarker Discovery and Quantifying It by PK/PD Modeling

Brink

Wong

Gülave

et al. 2016

AAPS J

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Abstract.To reveal unknown and potentially important mechanisms of drug action, multibiomarker discovery approaches are increasingly used. Time-course relationships between drug action and multi-biomarker profiles, however, are typically missing, while such relationships will provide increased insight in the underlying body processes. The aim of this study was to investigate the effect of the dopamine D2 antagonist remoxipride on the neuroendocrine system. Different doses of remoxipride (0, 0.7, 5.2, or 14 mg/kg) were administered to rats by intravenous infusion. Serial brain extracellular fluid (brainECF) and plasma samples were collected and analyzed for remoxipride pharmacokinetics (PK). Plasma samples were analyzed for concentrations of the eight pituitary-related hormones as a function of time. A Mann-Whitney test was used to identify the responding hormones, which were further analyzed by pharmacokinetic/ pharmacodynamic (PK/PD) modeling. A three-compartment PK model adequately described remoxipride PK in plasma and brainECF. Not only plasma PRL, but also adrenocorticotrophic hormone (ACTH) concentrations were increased, the latter especially at higher concentrations of remoxipride. Brain-derived neurotropic factor (BDNF), follicle stimulating hormone (FSH), growth hormone (GH), luteinizing hormone (LH), and thyroid stimulating hormones (TSH) did not respond to remoxipride at the tested doses, while oxytocin (OXT) measurements were below limit of quantification. Precursor pool models were linked to brainECF remoxipride PK by E max drug effect models, which could accurately describe the PRL and ACTH responses. To conclude, this study shows how a multi-biomarker identification approach combined with PK/PD modeling can reveal and quantify a neuroendocrine multi-biomarker response for single drug action.

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Binding characteristics of remoxipride and its metabolites to dopamine D2 and D3 receptors

Cited by 46 publications

References 15 publications

The atypical antipsychotic, remoxipride, blocks phencyclidine-induced disruption of prepulse inhibition in the rat

The atypical antipsychotic, remoxipride, blocks phencyclidine-induced disruption of prepulse inhibition in the rat

(−)Alprenolol potentiates the disrupting effects of dizocilpine on sensorimotor function in the rat

Revealing the Neuroendocrine Response After Remoxipride Treatment Using Multi-Biomarker Discovery and Quantifying It by PK/PD Modeling

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