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 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 H₁ 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 D₂ and D₃ antagonism in [³⁵S]GTPγS binding assays, but stimulated inositol phosphate (IP) production (pEC₅₀ 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 (pEC₅₀ 8.58, E_max 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 (pK_b 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.