Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D3/D2 receptors

Ágai-Csongor, Éva; Domány, György; Nógrádi, Katalin; Galambos, János; Vágó, István; Keserü, György M.; Greiner, István; Laszlovszky, István; Gere, Anikó; Schmidt, Éva; Kiss, Béla; Vastag, Mónika; Tihanyi, Károly; Sághy, Katalin; Laszy, Judit; Gyertyán, István; Zájer-Balázs, Mária; Gémesi, Larisza; Kapás, Margit; Szombathelyi, Zsolt

doi:10.1016/j.bmcl.2012.03.104

Cited by 76 publications

(67 citation statements)

References 7 publications

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“…N,Ndimethylurea, Vraylar TM ) is one such orally active, putative antipsychotic which is described as a dopamine D3 receptor preferring D3/D2 receptor partial agonist (Ágai-Csongor et al, 2012;Caccia et al, 2013). In vitro ligand binding and functional studies show that cariprazine has 6-10 fold higher affinity for the human dopamine D3 than D2 receptor (Ki=0.085 and Ki=0.49 nM, respectively) and is a moderate affinity partial agonist at 5-HT1A receptors (Kiss et al, 2010).…”

Section: Cariprazine (Rgh-188; N′-[trans-4-[2-[4-(23-dichlorophenyl)mentioning

confidence: 99%

“…Both gene polymorphisms and increased postmortem brain D3 receptor protein levels have also been associated with patients who had schizophrenia. Furthermore converging evidence showing the receptors have contrasting roles on cognition in rodents, encouraged development of drugs with differential D2/D3 receptor pharmacology (Millan and Brocco, 2008; Sokoloff et al, 2006; Watson et al, 2012a).N,Ndimethylurea, Vraylar TM ) is one such orally active, putative antipsychotic which is described as a dopamine D3 receptor preferring D3/D2 receptor partial agonist (Ágai-Csongor et al, 2012; Caccia et al, 2013). In vitro ligand binding and functional studies show that cariprazine has 6-10 fold higher affinity for the human dopamine D3 than D2 receptor (Ki=0.085 and Ki=0.49 nM, respectively) and is a moderate affinity partial agonist at 5-HT1A receptors (Kiss et al, 2010).…”

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The dopamine D 3 -preferring D 2 /D 3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia

Watson

King

Gyertyán

et al. 2016

European Neuropsychopharmacology

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. (2016) The dopamine D3-preferring D2/D3 dopamine receptor partial agonist, cariprazine, reverses behavioral changes in a rat neurodevelopmental model for schizophrenia. European Neuropsychopharmacology, 26 . pp. 208-224. ISSN 1873-7862 Access from the University of Nottingham repository: http://eprints.nottingham.ac.uk/34643/1/Fone%20cariprazine %20EurNeuropsych2016%20epub.pdf Copyright and reuse:The Nottingham ePrints service makes this work by researchers of the University of Nottingham available open access under the following conditions. This article is made available under the Creative Commons Attribution Non-commercial No Derivatives licence and may be reused according to the conditions of the licence. For more details see: http://creativecommons.org/licenses/by-nc-nd/2.5/ A note on versions:The version presented here may differ from the published version or from the version of record. If you wish to cite this item you are advised to consult the publisher's version. Please see the repository url above for details on accessing the published version and note that access may require a subscription.For more information, please contact eprints@nottingham.ac.ukThe dopamine D3-preferring D2/D3 dopamine receptor partial agonist, cariprazine, reverses behavioral changes in a rat neurodevelopmental model for schizophrenia Current antipsychotic medication is largely ineffective against the negative and cognitive symptoms of schizophrenia. One promising therapeutic development is to design new molecules that balance actions on dopamine D2 and D3 receptors to maximise benefits and limit adverse effects. This study used two rodent paradigms to investigate the action of the dopamine D3-preferring D3/D2 receptor partial agonist cariprazine. In adult male rats, cariprazine (0.03-0.3mg/kg i.p.), and the atypical antipsychotic aripiprazole (1-3mg/kg i.p.) caused dose-dependent reversal of a delay-induced impairment in novel object recognition (NOR). Treating neonatal rat pups with phencyclidine (PCP) and subsequent social isolation produced a syndrome of behavioral alterations in adulthood including hyperactivity in a novel arena, deficits in NOR and fear motivated learning and memory, and a reduction and change in pattern of social interaction accompanied by increased ultrasonic vocalisations (USVs).Acute administration of cariprazine (0.1 and 0.3mg/kg) and aripiprazole (3mg/kg) to resultant adult rats reduced neonatal PCP-social isolation induced locomotor hyperactivity and reversed NOR deficits. Cariprazine (0.3mg/kg) caused a limited reversal of the social interaction deficit but neither drug affected the change in USVs or the deficit in fear motivated learning and memory. Results suggest that in the behavioral tests investigated cariprazine is at least as effective as aripiprazole and in some paradigms it showed additional beneficial features further supporting the advantage of combined dopamine D3/D2 receptor targeting. These findings support recent clinical studies demonstrating the efficacy of cariprazine in tr...

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Section: Cariprazine (Rgh-188; N′-[trans-4-[2-[4-(23-dichlorophenyl)mentioning

confidence: 99%

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confidence: 99%

The dopamine D 3 -preferring D 2 /D 3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia

Watson

King

Gyertyán

et al. 2016

European Neuropsychopharmacology

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“…A PubMed search was conducted on 31 October 2012 using the search terms 'cariprazine,' 'RGH-188,' and 'RGH 188' without any date or language restrictions. The resulting 15 publications [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19] and their reference lists were then specifically examined for primary sources of information with emphasis on the drug metabolism and pharmacokinetics of cariprazine in humans. Query of www.clinicaltrials.gov on 31 October 2012 yielded 18 separate records (see Table 1); however for the clinical trials that were completed, study results were not posted.…”

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Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability

Citrome

2013

Expert Opinion on Drug Metabolism & Toxicology

114

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Cariprazine is a dopamine D3-preferring D3/D2 receptor partial agonist. Doses ≥ 1.5 mg/d yielded 69 - 75% D2/D3 receptor occupancy as measured in positron emission tomography scans. Mean half-life for cariprazine was 2 - 5 d over a dose range of 1.5 - 12.5 mg. Cariprazine produces two clinically relevant metabolites: desmethyl-cariprazine and didesmethyl-cariprazine, the latter having a longer half-life than cariprazine. Exposure to didesmethyl-cariprazine exceeded that of the parent drug. Cariprazine is metabolized by CYP3A4 and to a lesser extent by CYP2D6. The efficacy and safety of cariprazine have been so far investigated only in a few short-term (unpublished) clinical trials; however, three studies in schizophrenia and three studies in bipolar mania/mixed episodes evidenced a statistically significant therapeutic effect compared to placebo for cariprazine at doses ranging from 1.5 to 12 mg/d. There does not appear to be clinically relevant adverse effects of cariprazine on metabolic variables. Commonly encountered adverse events associated with cariprazine include insomnia, extrapyramidal symptoms, akathisia, sedation, nausea, dizziness, and constipation.

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“…It acts as a D2R and D3R partial agonist, with high selectivity towards the D3R; the reported Ki values are 0.5 nM for D2R and 0.1 nM for D3R(Agai-Csongor et al, 2012;Kiss et al, 2010) thus, at least theoretically, cariprazine should act as an antagonist at DR in presence of high dopamine levels, whereas would stimulate DR when in the presence of low dopamine level.…”

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Current drug treatments targeting dopamine D3 receptor

Leggio

Bucolo

Platania

et al. 2016

Pharmacology & Therapeutics

129

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Discovery of cariprazine (RGH-188): A novel antipsychotic acting on dopamine D3/D2 receptors

Cited by 76 publications

References 7 publications

The dopamine D 3 -preferring D 2 /D 3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia

The dopamine D 3 -preferring D 2 /D 3 dopamine receptor partial agonist, cariprazine, reverses behavioural changes in a rat neurodevelopmental model for schizophrenia

Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability

Current drug treatments targeting dopamine D3 receptor

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