RT Journal Article
SR Electronic
T1 Cariprazine (RGH-188), a Dopamine D<sub>3</sub> Receptor-Preferring, D<sub>3</sub>/D<sub>2</sub> Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 328
OP 340
DO 10.1124/jpet.109.160432
VO 333
IS 1
A1 Béla Kiss
A1 Attila Horváth
A1 Zsolt Némethy
A1 Éva Schmidt
A1 István Laszlovszky
A1 Gyula Bugovics
A1 Károly Fazekas
A1 Katalin Hornok
A1 Szabolcs Orosz
A1 István Gyertyán
A1 Éva Ágai-Csongor
A1 György Domány
A1 Károly Tihanyi
A1 Nika Adham
A1 Zsolt Szombathelyi
YR 2010
UL http://jpet.aspetjournals.org/content/333/1/328.abstract
AB 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.