Pharmacology and Drug Safety Research, Gedeon Richter Plc, Gyömrői u. 19-21, 1103 Budapest, Hungary.
Neurochem Int. 2011 Nov;59(6):925-35. doi: 10.1016/j.neuint.2011.07.002. Epub 2011 Jul 13.
We investigated the in vivo effects of orally administered cariprazine (RGH-188; trans-N-{4-[2-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-ethyl]-cyclohexyl}-N',N'-dimethyl-urea), a D(3)/D(2) dopamine receptor partial agonist with ∼10-fold preference for the D(3) receptor. Oral bioavailability of cariprazine at a dose of 1mg/kg in rats was 52% with peak plasma concentrations of 91ng/mL. Cariprazine 10mg/kg had good blood-brain barrier penetration, with a brain/plasma AUC ratio of 7.6:1. In rats, cariprazine showed dose-dependent in vivo displacement of (3)H-PHNO, a dopamine D(3) receptor-preferring radiotracer, in the D(3) receptor-rich region of cerebellar lobules 9 and 10. Its potent inhibition of apomorphine-induced climbing in mice (ED(50)=0.27mg/kg) was sustained for 8h. Cariprazine blocked amphetamine-induced hyperactivity (ED(50)=0.12mg/kg) and conditioned avoidance response (CAR) (ED(50)=0.84mg/kg) in rats, and inhibited the locomotor-stimulating effects of the noncompetitive NMDA antagonists MK-801 (ED(50)=0.049mg/kg) and phencyclidine (ED(50)=0.09mg/kg) in mice and rats, respectively. It reduced novelty-induced motor activity of mice (ED(50)=0.11mg/kg) and rats (ED(50)=0.18mg/kg) with a maximal effect of 70% in both species. Cariprazine produced no catalepsy in rats at up to 100-fold dose of its CAR inhibitory ED(50) value. Cariprazine 0.02-0.08mg/kg significantly improved the learning performance of scopolamine-treated rats in a water-labyrinth learning paradigm. Though risperidone, olanzapine, and aripiprazole showed antipsychotic-like activity in many of these assays, they were less active against phencyclidine and more cataleptogenic than cariprazine, and had no significant effect in the learning task. The distinct in vivo profile of cariprazine may be due to its higher affinity and in vivo binding to D(3) receptors versus currently marketed typical and atypical antipsychotics.
我们研究了经口给予卡利培嗪（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）的体内作用，这是一种 D(3)/D(2)多巴胺受体部分激动剂，对 D(3)受体的亲和力约为 10 倍。卡利培嗪在 1mg/kg 剂量下在大鼠体内的生物利用度为 52%，血浆峰浓度为 91ng/mL。卡利培嗪 10mg/kg 具有良好的血脑屏障穿透性，脑/血浆 AUC 比值为 7.6:1。在大鼠中，卡利培嗪显示出剂量依赖性的体内置换[3H]（+）-PHNO，一种多巴胺 D(3)受体优先示踪剂，在小脑小叶 9 和 10 中富含 D(3)受体的区域。它对阿扑吗啡诱导的小鼠攀爬（ED(50)=0.27mg/kg）的强烈抑制作用可持续 8 小时。卡利培嗪阻断了安非他命诱导的多动（ED(50)=0.12mg/kg）和条件性回避反应（CAR）（ED(50)=0.84mg/kg）在大鼠中，并抑制了非竞争性 NMDA 拮抗剂 MK-801（ED(50)=0.049mg/kg）和苯环利定（ED(50)=0.09mg/kg）在小鼠和大鼠中的运动刺激作用，分别。它降低了新奇诱导的小鼠（ED(50)=0.11mg/kg）和大鼠（ED(50)=0.18mg/kg）的运动活性，在两种物种中均产生 70%的最大效应。卡利培嗪在其 CAR 抑制 ED(50)值的 100 倍剂量下，在大鼠中未产生僵住。卡利培嗪 0.02-0.08mg/kg 显著改善了东莨菪碱处理的大鼠在水迷宫学习范式中的学习表现。尽管利培酮、奥氮平和阿立哌唑在这些测定中显示出类似抗精神病的活性，但它们对苯环利定的活性较低，比卡利培嗪更易引起僵住，并且在学习任务中没有显著影响。卡利培嗪的独特体内特征可能与其对 D(3)受体的更高亲和力和体内结合有关，而不是目前市场上的典型和非典型抗精神病药。
