Department of Molecular Pharmacology, Gedeon Richter Plc., P.O. Box 27., Budapest, H-1475 Hungary.
J Pharmacol Exp Ther. 2010 Apr;333(1):328-40. doi: 10.1124/jpet.109.160432. Epub 2010 Jan 21.
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.
卡利培嗪{ RGH-188; 反式-N-[4-[2-[4-(2,3-二氯苯基)哌嗪-1-基]乙基]环己基]-N',N'-二甲基脲盐酸盐}，一种新型候选抗精神病药物，对人类 D(3)受体的亲和力约为人类 D(2L)和 D(2S)受体的 10 倍（pKi 分别为 10.07、9.16 和 9.31）。它对人类 5-羟色胺（5-HT）2B 受体具有高亲和力（pK(i) 9.24），表现为纯拮抗作用。卡利培嗪对人类和大鼠海马 5-HT(1A)受体的亲和力较低（pK(i) 分别为 8.59 和 8.34），并显示出低内在效能。卡利培嗪对人类 5-HT(2A)受体的亲和力较低（pK(i) 7.73）。对组胺 H(1)和 5-HT(2C)受体的中等或低亲和力（pK(i) 分别为 7.63 和 6.87）表明卡利培嗪不太可能引起与这些受体相关的不良反应。卡利培嗪在多巴胺受体上表现出不同的功能谱，这取决于测定系统。它在[(35)S]GTPγS 结合测定中显示出 D(2)和 D(3)拮抗作用，但在表达人 D(2L)受体的鼠细胞中刺激肌醇磷酸（IP）产生（pEC(50) 8.50，E(max) 30%）和拮抗（+/-）-喹吡罗诱导的 IP 积累（pK(b) 9.22）。它具有部分激动活性（pEC(50) 8.58，E(max) 71%），通过抑制表达人 D(3)受体的中国仓鼠卵巢细胞中环磷酸腺苷（cAMP）的积累，并能有效拮抗 R(+)-2-二丙基氨基-7-羟基-1,2,3,4-四氢萘并[1,2,3-de]喹嗪-8-醇 HBr（7-OH-DPAT）诱导的 cAMP 形成抑制（pK(b) 9.57）。在这些功能测定中，与阿立哌唑相比，卡利培嗪显示出类似（D(2))或更高（D(3))的拮抗剂-部分激动剂亲和力和更大的（3-至 10 倍）D(3)对 D(2)选择性。在体内转化和生物合成实验中，卡利培嗪表现出 D(2)相关的部分激动剂和拮抗剂特性，这取决于实际的多巴胺能紧张度。卡利培嗪在 D(3)和 D(2)受体上的拮抗剂-部分激动剂特性，具有非常高和优先的 D(3)受体亲和力，使其成为一种具有独特药理学特征的候选抗精神病药物，与已知的抗精神病药物不同。
