TY - JOUR 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 DO - 10.1124/jpet.109.160432 SP - jpet.109.160432 AU - Bela Kiss AU - Attila Horvath AU - Zsolt Nemethy AU - Eva Schmidt AU - Istvan Laszlovszky AU - Gyula Bugovics AU - Karoly Fazekas AU - Katalin Hornok AU - Szabolcs Orosz AU - Istvan Gyertyan AU - Eva Agai-Csongor AU - Gyorgy Domany AU - Karoly Tihanyi AU - Nika Adham AU - Zsolt Szombathelyi Y1 - 2010/01/01 UR - http://jpet.aspetjournals.org/content/early/2010/01/21/jpet.109.160432.abstract N2 - 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 hD2L and hD2S receptors (pKi: 10.07, 9.16, 9.31, respectively). It displayed high affinity at h5-HT2B 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 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 CHO cells expressing hD3 receptors and potently antagonized 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.The American Society for Pharmacology and Experimental Therapeutics ER -