| CAS |
No.839712-12-8 |
| 中文名称 |
卡利拉嗪 |
| 英文名称 |
Cariprazine |
| 别名 |
RGH-188 |
| 分子式 |
C21H32Cl2N4O |
| 分子量 |
427.41 |
| 溶解性 |
Soluble in DMSO ≥0.1mg/mL(Need ultrasonic or Water bath) |
| 纯度 |
≥98% |
| 外观(性状) |
White to brown Solid |
| 储存条件 |
Powder:2-8℃，2 years |
| 运输条件 |
冷藏运输 |
| 靶点 |
Dopamine Receptor;5-HT1A |
| 通路 |
Neuronal Signaling;GPCR & G Protein |
| 背景说明 |
Cariprazine可以结合D3, D2 和 5-HT1A，可用于抗精神病方向的研究。 |
| 生物活性 |
Cariprazine is a novel antipsychotic agent candidate that exhibits high affinity for the D3 (Ki=0.085 nM) and D2 (Ki=0.49 nM) receptors， and moderate affinity for the 5-HT1A receptor (Ki=2.6 nM).[1-4] |
| In Vitro |
Cariprazine stimulates inositol phosphate (IP) formation with a high potency (pEC50 8.5) with relatively low efficacy (Emax 30%)[2]. Cariprazine， 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). Cariprazine displays high affinity at human serotonin (5-HT) type 2B receptors (pKi 9.24) with pure antagonism. Cariprazine has lower affinity at human and rat hippocampal 5-HT1A receptors (pKi 8.59 and 8.34， respectively) and demonstrates low intrinsic efficacy. Cariprazine displays 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 Cariprazines reduced propensity for adverse events related to these receptors[2]. Cariprazine is over sixfold more potent (EC50=1.4 nM) than Aripiprazole (EC50=9.2 nM) in inhibiting isoproterenol-induced cAMP production in HEK-293 cells[4]. |
| In Vivo |
Administration of Cariprazine (30 μg/kg) reduces the striatal uptake of both radioligands to the level of nonspecific binding compared with baseline PET measurements. Cariprazine has negligible effect on the time-activity curves in the cerebellum. At doses of 5.0 and 30 μg/kg， Cariprazine causes a dose-dependent dopamine D2/D3 receptor occupancy of ~45% and ~80% for both antagonist [11C] raclopride and agonist radioligand [11C]MNPA. Receptor occupancy of dopamine D2/D3 receptors calculated using the transient equilibrium and the MRTM2 methods ranged from 5% at the lowest dose (1.0 μg/kg) to 94% at the highest dose (300 μg/kg)[1]. The effects of 5 doses of Cariprazine (ranging from 0.005 to 0.15 mg/kg) are examined on EPM behavior of wild-type mice. Whereas lower doses of Cariprazine (0.005 to 0.02 mg/kg) do not alter the time spent in open arms， the two higher doses (0.08 and 0.15 mg/kg) lead to a significant decline of this measure (ANOVA， (F(5，52)=4.20; p=0.0032)). Moreover， the two higher doses of Cariprazine also lead to a significant decrease in the total number of arm entries (F(5，52)=7.21; p=0.0001)) but this decrease in the total number of arm entries is largely accounted for by a significant decrease in the number of closed arm entries (F(5，52)=11.75; p=0.0001)). The two highest doses of Cariprazine (0.08 and 0.15 mg/kg) have significant effects on locomotor activity， but doses ranging from 0.005 to 0.02 mg/kg do not affect anxiety-like behavior or locomotor activity in the EPM test[3]. A significant (P[4]. |
| 细胞实验 |
Cells are seeded on a 24-well tissue culture plate in 500 μL of medium. Fifty microliters of medium containing 0.55 μCi myo-[3H]inositol is added (final concentration 1 μCi/mL) and incubated for 18-20 h. Cells are then washed three times with buffer containing 140 mM NaCl， 5 mM KCl， 2 mM CaCl2， 5 mM HEPES， 5 mM Na-HEPES， 20 mM glucose， and 10 mM LiCl (pH 7.4). Cells are then incubated for an additional 60 min (37°C) in medium with test compounds alone (agonist test) or alongside 1000 nM (±)-Quinpirole (antagonist test). Medium is then aspirated off， cells are lysed by adding 400 μL of 0.1 M HCl/2 mM CaCl2， and supernatants are frozen at ?72°C. After thawing and centrifugation at 1000g for 10 min， 200 μL of each supernatant is loaded on 250 μL of AG1-X8 (formate form) anion exchange column. Effluent is discarded， and columns are washed twice in 1.5 mL of distilled water. IPs are eluted with 2.5 mL of 1 M ammonium formate/0.1 M formic acid directly into scintillation vials， 10 mL of Optiphase HiSafe 3 is added， and the radioactivity is determined in a TriCarb 4900 scintillation counter[2]. |
| 动物实验 |
Mice[3] Experiments are performed on wild-type C57Bl/6J mice. In tests of cognitive functions， it is essential to employ concentrations of drugs that have no effects on emotional behavior and that do not impair locomotor activity. Whether Cariprazine (administered at a dose range of 0.005 to 0.15 mg/kg) is first tested affected the behavior of mice in the EPM， a test of anxiety-related behavior that is also critically dependent upon normal locomotor activity. Animals are exposed to an EPM apparatus designed for mice (leg height: 45 cm， arm length: 35 cm， lane width: 5 cm， wall height: 15 cm). Testing (under 100 lux lighting) is performed between 1 and 4 PM. Mice are placed in the center of the maze and their time spent in open arms and the number of closed and open arm entries during a 5 min test period is recorded. Measures of the time spent in open arms and the number of open arm entries served as a measure of anxiety-like behavior. The number of closed arm entries served as a measure of locomotor activity. Rats[4] Adult male Sprague-Dawley rats (150-300 g) are used. Cariprazine is dissolved in 0.9% saline and administered at 0.06， 0.25， 0.5， and 1.0 mg/kg via intraperitoneal (i.p.) injection 1 h before i.c.v. injection of ouabain and daily thereafter for 7 days. Open field activity is assessed immediately following the i.c.v. injection and again after 7 days (the activity is noted 10-14 h after the last i.p. injection of Cariprazine). |
| 激酶实验 |
These assays are done in 50 mM Tris (pH 7.4)， 100 mM NaCl， 7 mM MgCl2， 1 mM EDTA， and 1 mM DTT. Assay tubes (final volume 250 μL) contain 50 μM (striatum and hippocampus) or 1 μM (D2 and D3 cell membrane) GDP， the ligand to be examined， and membrane suspension (250 μg tissue/tube for the striatum and hippocampus and 20 μg protein/tube for hD2 and hD3 membranes). Samples are preincubated for 10 min at 30°C. After the addition of 50 pM [35S]GTPγS， membranes are incubated for an additional 60 min at 30°C. Nonspecific binding is determined in the presence of 10 μM GTPγS; basal binding is determined in the presence of buffer only. The assay is terminated by rapid filtration through UniFilter GF/B using a harvester， and the membranes washed four times with 1 mL of ice-cold buffer. After drying (40°C for 1 h)， 40 μL of Microscint is added to the filters， and the bound radioactivity is determined by a TopCount NXT counter[2]. |
| 数据来源文献 |
[1]. Seneca N， et al. Occupancy of dopamine D2 and D3 and serotonin 5-HT1A receptors by the novel antipsychotic drug candidate， cariprazine (RGH-188)， in monkey brain measured using positron emission tomography. Psychopharmacology (Berl). 2011 Dec;218(3):579-8
[2]. Kiss B， et al. Cariprazine (RGH-188)， a dopamine D(3) receptor-preferring， D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010 Apr;333(1):328-40.
[3]. Zimnisky R， et al. Cariprazine， a dopamine D(3)-receptor-preferring partial agonist， blocks phencyclidine-induced impairments of working memory， attention set-shifting， and recognition memory in the mouse. Psychopharmacology (Berl). 2013 Mar;226(1):91-100
[4]. Gao Y， et al. Cariprazine exerts antimanic properties and interferes with dopamine D2 receptor β-arrestin interactions. Pharmacol Res Perspect. 2015 Feb;3(1):e00073. |
| 规格 |
1mg 2mg 5mg 10mg 25mg 50mg |
| 单位 |
瓶 |
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