title: Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile.
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 D(3) versus human D(2L) and human D(2S) receptors (pKi 10.07, 9.16, and 9.31, respectively). It displayed high affinity at human serotonin (5-HT) type 2B receptors (pK(i) 9.24) with pure antagonism. Cariprazine had lower affinity at human and rat hippocampal 5-HT(1A) receptors (pK(i) 8.59 and 8.34, respectively) and demonstrated low intrinsic efficacy. Cariprazine displayed low affinity at human 5-HT(2A) receptors (pK(i) 7.73). Moderate or low affinity for histamine H(1) and 5-HT(2C) receptors (pK(i) 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 D(2) and D(3) antagonism in [(35)S]GTPgammaS binding assays, but stimulated inositol phosphate (IP) production (pEC(50) 8.50, E(max) 30%) and antagonized (+/-)-quinpirole-induced IP accumulation (pK(b) 9.22) in murine cells expressing human D(2L) receptors. It had partial agonist activity (pEC(50) 8.58, E(max) 71%) by inhibiting cAMP accumulation in Chinese hamster ovary cells expressing human D(3) receptors and potently antagonized R(+)-2-dipropylamino-7-hydroxy-1,2,3,4-tetrahydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK(b) 9.57). In these functional assays, cariprazine showed similar (D(2)) or higher (D(3)) antagonist-partial agonist affinity and greater (3- to 10-fold) D(3) versus D(2) selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D(2)-related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D(3) and D(2) receptors, with very high and preferential affinity to D(3) receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics.
authors.affiliation: Department of Molecular Pharmacology, Gedeon Richter Plc., P.O. Box 27., Budapest, H-1475 Hungary. b.kiss@richter.hu
authors.forename: Béla
authors.initials: B
authors.lastname: Kiss
authors.forename: Attila
authors.initials: A
authors.lastname: Horváth
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Némethy
authors.forename: Eva
authors.initials: E
authors.lastname: Schmidt
authors.forename: István
authors.initials: I
authors.lastname: Laszlovszky
authors.forename: Gyula
authors.initials: G
authors.lastname: Bugovics
authors.forename: Károly
authors.initials: K
authors.lastname: Fazekas
authors.forename: Katalin
authors.initials: K
authors.lastname: Hornok
authors.forename: Szabolcs
authors.initials: S
authors.lastname: Orosz
authors.forename: István
authors.initials: I
authors.lastname: Gyertyán
authors.forename: Eva
authors.initials: E
authors.lastname: Agai-Csongor
authors.forename: György
authors.initials: G
authors.lastname: Domány
authors.forename: Károly
authors.initials: K
authors.lastname: Tihanyi
authors.forename: Nika
authors.initials: N
authors.lastname: Adham
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Szombathelyi
mesh_terms: D015107:4-Butyrolactone / Q000494:pharmacology; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D000068180:Aripiprazole; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D000242:Cyclic AMP / Q000096:biosynthesis; D004298:Dopamine / Q000378:metabolism; D065127:Dopamine D2 Receptor Antagonists; D054333:Drug Partial Agonism; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D007295:Inositol Phosphates / Q000096:biosynthesis; D008297:Male; D051379:Mice; D010879:Piperazines / Q000494:pharmacology*; D015363:Quinolones / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D050637:Receptors, Dopamine D3 / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011969:Receptors, Histamine H1 / Q000378:metabolism; D011985:Receptors, Serotonin / Q000378:metabolism; D011994:Recombinant Proteins / Q000819:agonists / Q000037:antagonists & inhibitors; D012110:Reserpine / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism
chemical_list: D014150:Antipsychotic Agents; D065127:Dopamine D2 Receptor Antagonists; D007295:Inositol Phosphates; D010879:Piperazines; D015363:Quinolones; D050637:Receptors, Dopamine D3; D011969:Receptors, Histamine H1; D011985:Receptors, Serotonin; D011994:Recombinant Proteins; D012701:Serotonin; D000068180:Aripiprazole; D012110:Reserpine; D000242:Cyclic AMP; C533287:cariprazine; D015107:4-Butyrolactone; D004298:Dopamine