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Research ArticleNEUROPHARMACOLOGY

Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Béla Kiss, Attila Horváth, Zsolt Némethy, Éva Schmidt, István Laszlovszky, Gyula Bugovics, Károly Fazekas, Katalin Hornok, Szabolcs Orosz, István Gyertyán, Éva Ágai-Csongor, György Domány, Károly Tihanyi, Nika Adham and Zsolt Szombathelyi
Journal of Pharmacology and Experimental Therapeutics April 2010, 333 (1) 328-340; DOI: https://doi.org/10.1124/jpet.109.160432
Béla Kiss
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Attila Horváth
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Zsolt Némethy
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Éva Schmidt
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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István Laszlovszky
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Gyula Bugovics
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Károly Fazekas
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Katalin Hornok
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Szabolcs Orosz
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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István Gyertyán
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Éva Ágai-Csongor
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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György Domány
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Károly Tihanyi
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Nika Adham
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Zsolt Szombathelyi
Research and Development, Gedeon Richter Plc., Budapest, Hungary (B.K., A.H., Z.N., E.S., I.L., G.B., K.F., K.H., S.O., I.G., E.A.-C., G.D., K.T., Z.S.); and Forest Research Institute, Division of Forest Laboratories Inc., Jersey City, New Jersey (N.A.)
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Abstract

Cariprazine {RGH-188; trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea hydrochloride}, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D3 versus human D2L and human D2S receptors (pKi 10.07, 9.16, and 9.31, respectively). It displayed high affinity at human serotonin (5-HT) type 2B receptors (pKi 9.24) with pure antagonism. Cariprazine had lower affinity at human and rat hippocampal 5-HT1A receptors (pKi 8.59 and 8.34, respectively) and demonstrated low intrinsic efficacy. Cariprazine displayed low affinity at human 5-HT2A receptors (pKi 7.73). Moderate or low affinity for histamine H1 and 5-HT2C receptors (pKi 7.63 and 6.87, respectively) suggest cariprazine's reduced propensity for adverse events related to these receptors. Cariprazine demonstrated different functional profiles at dopamine receptors depending on the assay system. It displayed D2 and D3 antagonism in [35S]GTPγS binding assays, but stimulated inositol phosphate (IP) production (pEC50 8.50, Emax 30%) and antagonized (±)-quinpirole-induced IP accumulation (pKb 9.22) in murine cells expressing human D2L receptors. It had partial agonist activity (pEC50 8.58, Emax 71%) by inhibiting cAMP accumulation in Chinese hamster ovary cells expressing human D3 receptors and potently antagonized R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pKb 9.57). In these functional assays, cariprazine showed similar (D2) or higher (D3) antagonist–partial agonist affinity and greater (3- to 10-fold) D3 versus D2 selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D2-related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist–partial agonist properties of cariprazine at D3 and D2 receptors, with very high and preferential affinity to D3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics.

Footnotes

    • Received August 13, 2009.
    • Accepted January 19, 2010.
  • Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.

    doi:10.1124/jpet.109.160432.

  • ABBREVIATIONS:

    Cariprazine (RGH-188)
    trans-N-[4-[2-[4-(2,3-dichlorophenyl)piperazin-1-yl]ethyl]cyclohexyl]-N′,N′-dimethylurea hydrochloride
    5-HT
    serotonin
    5-HIAA
    5-hydroxyindolyl acetic acid
    hD2
    human D2
    hD3
    human D3
    DA
    dopamine
    DOPA
    3,4-dihydroxyphenylalanine
    DOPAC
    3,4-dihydroxyphenyl acetic acid
    GBL
    γ-butyrolactone
    HVA
    homovanillic acid
    L741626
    3-[[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole
    SB-277011
    trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydro-2-isoquinolinyl)ethyl]cyclohexyl]quinoline-4-carboxamide
    NSD-1015
    3-hydroxy-benzylhydrazine HCl
    7-OH-DPAT
    R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr
    8-OH-DPAT
    R(+)-2-dipropylamino-8-hydroxy-1,2,3,4-tetrahydronaphtalene HBr
    DOI
    (−)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane HCl
    IP
    inositol phosphate
    DMEM
    Dulbecco's modified Eagle's medium
    CHO
    Chinese hamster ovary
    HEK
    human embryonic kidney
    APM
    apomorphine
    DTT
    dithiotreithol
    S33084
    (3aR,9bS)-N-[4-(8-cyano-1,3a,4,9b-tetrahydro-3H-benzopyrano[3,4-c]pyrrole-2-yl)-butyl]-(4-phenyl) benzamide
    S33138
    N-[4-[2-[(3aS,9bR)-8-cyano-1,3a,4,9b-tetrahydro[1]-benzopyrano[3,4-c]pyrrol-2(3H)-yl)ethyl]phenacetamide
    RG-15
    trans-N-{4-[2-[4-(3-cyano-5-trifluoromethyl-phenyl)-piperazine-1-yl]-ethyl]-cyclohexyl}-3-pyridinesulfonic amide dihydrochloride
    (+)-PHNO
    trans-1a,2,3,4a,5,6-hexahydro-9-hydroxy-4-propyl-4H-naphtho[1,2-b]-1,4-oxazine
    SDZ-208-911
    N-[(8a)-2,6-dimethylergoline-8-yl]-2,2-diethylpopanamide
    SDZ-208-912
    N-[(8a)-2-chloro-6-methylergoline-8-yl]-2,2-diethylpropanamide
    MK-912
    (2S,12bS)-1′,3′-dimethylspiro[1,3,4,5′,6,6′,7,12b-octahydro-2H-benzo[b]furo[2,3-a]quinolizine-2,4′-pyrimidin]-2′-one
    RTI-55
    (−)-3β-(4-iodophenyl)tropane-2β-carboxylic acid methyl ester
    SB-204741
    N-(1-methyl-1H-indolyl-5-yl)-N′′-(3-methyl-5-isothiazolyl)urea
    G418
    (2R,3S,4R,5R,6S)-5-amino-6-[(1R,2S,3S,4R,6S)-4,6-diamino-3-[(2R,3R,4R,5R)-3,5-dihydroxy-5-methyl-4-methylaminooxan-2-yl]oxy-2-hydroxycyclohexyl]oxy-2-(1-hydroxyethyl)oxane-3,4-diol.

  • Copyright © 2010 by The American Society for Pharmacology and Experimental Therapeutics
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Research ArticleNEUROPHARMACOLOGY

Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Béla Kiss, Attila Horváth, Zsolt Némethy, Éva Schmidt, István Laszlovszky, Gyula Bugovics, Károly Fazekas, Katalin Hornok, Szabolcs Orosz, István Gyertyán, Éva Ágai-Csongor, György Domány, Károly Tihanyi, Nika Adham and Zsolt Szombathelyi
Journal of Pharmacology and Experimental Therapeutics April 1, 2010, 333 (1) 328-340; DOI: https://doi.org/10.1124/jpet.109.160432

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Research ArticleNEUROPHARMACOLOGY

Cariprazine (RGH-188), a Dopamine D3 Receptor-Preferring, D3/D2 Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Béla Kiss, Attila Horváth, Zsolt Némethy, Éva Schmidt, István Laszlovszky, Gyula Bugovics, Károly Fazekas, Katalin Hornok, Szabolcs Orosz, István Gyertyán, Éva Ágai-Csongor, György Domány, Károly Tihanyi, Nika Adham and Zsolt Szombathelyi
Journal of Pharmacology and Experimental Therapeutics April 1, 2010, 333 (1) 328-340; DOI: https://doi.org/10.1124/jpet.109.160432
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