Cariprazine hydrochloride
(Synonyms: 盐酸卡利拉嗪; RGH188 hydrochloride) 目录号 : GC35610
An atypical antipsychotic
Cas No.:1083076-69-0
Sample solution is provided at 25 µL, 10mM.
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Quality Control & SDS
- View current batch:
- Purity: >98.50%
- COA (Certificate Of Analysis)
- SDS (Safety Data Sheet)
- Datasheet
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Kinase experiment: |
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]. |
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Cell experiment: |
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]. |
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Animal experiment: |
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). |
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References: [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 |
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Cariprazine is an atypical antipsychotic.1 It binds to dopamine D2L, D2S, and D3 receptors, the serotonin (5-HT) receptor subtypes 5-HT1A, 5-HT2A, and 5-HT2B, and histamine H1 and sigma-1 (σ1) receptors (Kis = 0.085-23.44 nM).2 Cariprazine is an antagonist of dopamine D2 and D3 receptors (Kbs = 0.759 and 0.316 nM, respectively, in dopamine-induced [35S]GTPγS binding assays). It is also a partial agonist at these receptors, stimulating inositol phosphate production in murine A9 cells expressing human D2L receptors (EC50 = 3.16 nM) and inhibiting forskolin-induced cAMP accumulation in CHO cells expressing human D3 receptors (EC50 = 2.63 nM). Cariprazine inhibits amphetamine-induced hyperactivity and the conditioned avoidance response in rats (ED50s = 0.12 and 0.84 mg/kg, respectively).3 It also inhibits scopolamine-induced learning deficits in a water labyrinth learning test in rats when administered at doses ranging from 0.02 to 0.08 mg/kg. Formulations containing cariprazine have been used in the treatment of schizophrenia, as well as manic, depressive, or mixed episodes associated with bipolar I disorder.
1.Mészáros, G.P., Agai-Csongor, E., and Kapás, M.Sensitive LC-MS/MS methods for the quantification of RGH-188 and its active metabolites, desmethyl- and didesmethyl-RGH-188 in human plasma and urineJ. Pharm. Biomed. Anal.48(2)388-397(2008) 2.Kiss, B., Horváth, A., Némethy, Z., et al.Cariprazine (RGH-188), a dopamine D3 receptor-preferring, D3/D2 dopamine receptor antagonist-partial agonist antipsychotic candidate: In vitro and neurochemical profileJ. Pharmacol. Exp. Ther.333(1)328-340(2010) 3.Gyertyán, I., Kiss, B., Sághy, K., et al.Cariprazine (RGH-188), a potent D3/D2 dopamine receptor partial agonist, binds to dopamine D3 receptors in vivo and shows antipsychotic-like and procognitive effects in rodentsNeurochem. Int.59(6)925-935(2011)
| Cas No. | 1083076-69-0 | SDF | |
| 别名 | 盐酸卡利拉嗪; RGH188 hydrochloride | ||
| Canonical SMILES | O=C(N[C@H]1CC[C@H](CCN2CCN(C3=CC=CC(Cl)=C3Cl)CC2)CC1)N(C)C.[H]Cl | ||
| 分子式 | C21H33Cl3N4O | 分子量 | 463.87 |
| 溶解度 | DMSO: 6.67 mg/mL (14.38 mM) | 储存条件 | Store at -20°C |
| General tips | 请根据产品在不同溶剂中的溶解度选择合适的溶剂配制储备液；一旦配成溶液，请分装保存，避免反复冻融造成的产品失效。 储备液的保存方式和期限：-80°C 储存时，请在 6 个月内使用，-20°C 储存时，请在 1 个月内使用。 为了提高溶解度，请将管子加热至37℃，然后在超声波浴中震荡一段时间。 |
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| Shipping Condition | 评估样品解决方案：配备蓝冰进行发货。所有其他可用尺寸：配备RT，或根据请求配备蓝冰。 | ||
| 制备储备液 | |||
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1 mg | 5 mg | 10 mg |
| 1 mM | 2.1558 mL | 10.7789 mL | 21.5578 mL |
| 5 mM | 0.4312 mL | 2.1558 mL | 4.3116 mL |
| 10 mM | 0.2156 mL | 1.0779 mL | 2.1558 mL |
| 第一步：请输入基本实验信息（考虑到实验过程中的损耗，建议多配一只动物的药量） | ||||||||||
| 给药剂量 | mg/kg |  |
动物平均体重 | g | |
每只动物给药体积 | ul | |
动物数量 | 只 |
| 第二步：请输入动物体内配方组成（配方适用于不溶于水的药物；不同批次药物配方比例不同，请联系GLPBIO为您提供正确的澄清溶液配方） | ||||||||||
| % DMSO % % Tween 80 % saline | ||||||||||
| 计算重置 | ||||||||||
计算结果:
工作液浓度： mg/ml；
DMSO母液配制方法： mg 药物溶于 μL DMSO溶液（母液浓度 mg/mL，
体内配方配制方法：取 μL DMSO母液，加入 μL PEG300，混匀澄清后加入μL Tween 80，混匀澄清后加入 μL saline，混匀澄清。
1. 首先保证母液是澄清的；
2.
一定要按照顺序依次将溶剂加入，进行下一步操作之前必须保证上一步操作得到的是澄清的溶液，可采用涡旋、超声或水浴加热等物理方法助溶。
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Canadian Network for Mood and Anxiety Treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) 2018 guidelines for the management of patients with bipolar disorder
Bipolar Disord 2018 Mar;20(2):97-170.PMID:29536616DOI:10.1111/bdi.12609.
The Canadian Network for Mood and Anxiety Treatments (CANMAT) previously published treatment guidelines for bipolar disorder in 2005, along with international commentaries and subsequent updates in 2007, 2009, and 2013. The last two updates were published in collaboration with the International Society for Bipolar Disorders (ISBD). These 2018 CANMAT and ISBD Bipolar Treatment Guidelines represent the significant advances in the field since the last full edition was published in 2005, including updates to diagnosis and management as well as new research into pharmacological and psychological treatments. These advances have been translated into clear and easy to use recommendations for first, second, and third- line treatments, with consideration given to levels of evidence for efficacy, clinical support based on experience, and consensus ratings of safety, tolerability, and treatment-emergent switch risk. New to these guidelines, hierarchical rankings were created for first and second- line treatments recommended for acute mania, acute depression, and maintenance treatment in bipolar I disorder. Created by considering the impact of each treatment across all phases of illness, this hierarchy will further assist clinicians in making evidence-based treatment decisions. Lithium, quetiapine, divalproex, asenapine, aripiprazole, paliperidone, risperidone, and Cariprazine alone or in combination are recommended as first-line treatments for acute mania. First-line options for bipolar I depression include quetiapine, lurasidone plus lithium or divalproex, lithium, lamotrigine, lurasidone, or adjunctive lamotrigine. While medications that have been shown to be effective for the acute phase should generally be continued for the maintenance phase in bipolar I disorder, there are some exceptions (such as with antidepressants); and available data suggest that lithium, quetiapine, divalproex, lamotrigine, asenapine, and aripiprazole monotherapy or combination treatments should be considered first-line for those initiating or switching treatment during the maintenance phase. In addition to addressing issues in bipolar I disorder, these guidelines also provide an overview of, and recommendations for, clinical management of bipolar II disorder, as well as advice on specific populations, such as women at various stages of the reproductive cycle, children and adolescents, and older adults. There are also discussions on the impact of specific psychiatric and medical comorbidities such as substance use, anxiety, and metabolic disorders. Finally, an overview of issues related to safety and monitoring is provided. The CANMAT and ISBD groups hope that these guidelines become a valuable tool for practitioners across the globe.
Augmentation strategies for treatment resistant major depression: A systematic review and network meta-analysis
J Affect Disord 2022 Apr 1;302:385-400.PMID:34986373DOI:10.1016/j.jad.2021.12.134.
Objective: To compare the efficacy and discontinuation of augmentation agents in adult patients with treatment-resistant depression (TRD). We conducted a systematic review and network meta-analyses (NMA) to combine direct and indirect comparisons of augmentation agents. Methods: We included randomized controlled trials comparing one active drug with another or with placebo following a treatment course up to 24 weeks. Nineteen agents were included: stimulants, atypical antipsychotics, thyroid hormones, antidepressants, and mood stabilizers. Data for response/remission and all-cause discontinuation rates were analyzed. We estimated effect-size by relative risk using pairwise and NMA with random-effects model. Results: A total of 65 studies (N = 12,415) with 19 augmentation agents were included in the NMA. Our findings from the NMA for response rates, compared to placebo, were significant for: liothyronine, nortriptyline, aripiprazole, brexpiprazole, quetiapine, lithium, modafinil, olanzapine (fluoxetine), Cariprazine, and lisdexamfetamine. For remission rates, compared to placebo, were significant for: thyroid hormone(T4), aripiprazole, brexpiprazole, risperidone, quetiapine, and olanzapine (fluoxetine). Compared to placebo, ziprasidone, mirtazapine, and Cariprazine had statistically significant higher discontinuation rates. Overall, 24% studies were rated as having low risk of bias (RoB), 63% had moderate RoB and 13% had high RoB. Limitations: Heterogeneity in TRD definitions, variable trial duration and methodological clinical design of older studies and small number of trials per comparisons. Conclusions: This NMA suggests a superiority of the regulatory approved adjunctive atypical antipsychotics, thyroid hormones, dopamine compounds (modafinil and lisdexamfetamine) and lithium. Acceptability was lower with ziprasidone, mirtazapine, and Cariprazine. Further research and head-to-head studies should be considered to strengthen the best available options for TRD.
Cariprazine to Treat Schizophrenia and Bipolar Disorder in Adults
Psychopharmacol Bull 2020 Sep 14;50(4):83-117.PMID:33012874doi
Purpose of review: Antipsychotics are the standard of care when it comes to the treatment of Schizophrenia, and they are often used in Bipolar as well. Their use can come with adverse effects such as extrapyramidal movements, metabolic complications as well as cardiovascular complications such as a prolonged QT interval. Treatment for these side effects ranges from the treatment of the complications up to the cessation of the medication, which could come at the expense of the user's stability. Both schizophrenia and bipolar disorder have an increased risk of suicide and increased morbidity. The purpose of this review presents the background, evidence, and indications for the use of the new second-generation antipsychotic Cariprazine, which has a primary function as a D3 and D2 partial agonist, with higher selectivity for the D3 receptor type. Recent findings: Schizophrenia is currently teated by dopamine antagonists and/or 5HT modulators, each with their own set of side effects. Bipolar disorder is mostly treated with mood stabilizers. Studies looking at the efficacy and safety of Cariprazine have shown in two phase II trials and phase III trials the decrease in PANSS scores in schizophrenia. The most common adverse effects were akathisia, insomnia, constipation, and other extrapyramidal side effects. A unique side effect of Cariprazine caused bilateral cataract and cystic degeneration of the retina in the dog following daily oral administration for 13 weeks and/or 1 year and retinal degeneration in rats following daily oral administration for 2 years. Another study showed that Cariprazine had significant efficacy in preventing relapse in patients with schizophrenia. The time to the loss of sustained remission was significantly longer (P = .0020) for Cariprazine compared to placebo (hazard ratio = 0.51) during the double-blind treatment. 60.5% of patients treated with Cariprazine and 34.9% of patients treated with placebo sustained remission through the final visit (odds ratio [OR] = 2.85; P = .0012; number needed to treat [NNT] = 4. Another Phase IIIb study looked at negative symptoms and used the Positive and Negative Syndrome Scale Factor Score for Negative Symptoms (PANSS-FSNS), and it found that the use of Cariprazine, from baseline to week 26, led to a greater least-squares mean change in PANSS-FSNS than did risperidone. Another study looked at the quality of life years with the treatment of Cariprazine and showed those treated with Cariprazine had superior quality of life compared to those treated with risperidone. In terms of bipolar disorder, it showed a decrease in depressive symptoms as measured by decreased MADRs scores with a dose of 3.0mg/day. A phase II study looked at the use of Cariprazine in mania or mix states and showed Cariprazine significantly decreased YMRS scores compared to placebo, least-square mean difference of -6.1 (p < 0.001). The metabolic parameters demonstrated comparable changes except for fasting glucose in which Cariprazine was associated with elevations in glucose levels compared to placebo (p < 0.05). Another phase III study showed significant differences in YMRS total score mean change between Cariprazine versus placebo-treated group. Changes in metabolic profiles in all mentioned studies were minimal. Summary: Cariprazine, in recent studies, has shown some promise in being able to treat both bipolar disorder in manic, depressed, and mixed states as well as schizophrenia. Side effects noted as adverse events in these studies are similar in profile to the medications that were developed in the past. With better relapse prevention, Cariprazine could be a reasonable alternative clozapine.
Cariprazine: A Review in Schizophrenia
CNS Drugs 2017 Jun;31(6):513-525.PMID:28560619DOI:10.1007/s40263-017-0442-z.
Cariprazine (Vraylar™) is a dopamine D3-preferring D2/D3 receptor partial agonist indicated for the treatment of patients with schizophrenia. This narrative review summarizes pharmacological, efficacy and tolerability data relevant to the use of Cariprazine in patients with this disorder. In 6-week, phase IIb and III trials in patients with schizophrenia, Cariprazine was significantly more efficacious than placebo in improving schizophrenia symptoms, including improvements in Positive and Negative Syndrome Scale (PANSS) total scores. It was associated with a significantly longer time to relapse than placebo in a long-term, phase III, relapse-prevention study. Cariprazine was also significantly more efficacious than risperidone in improving PANSS Factor Score for Negative Symptoms in a phase III trial in patients with predominantly negative symptoms of schizophrenia, a typically difficult to treat group of patients. Cariprazine was generally well tolerated in clinical trials, with most adverse events being of mild to moderate severity, and metabolic changes observed were considered generally not clinically significant. Cariprazine is a useful addition to the treatment options for schizophrenia, and may be of particular use in patients with predominantly negative symptoms.
Cariprazine, A Broad-Spectrum Antipsychotic for the Treatment of Schizophrenia: Pharmacology, Efficacy, and Safety
Adv Ther 2021 Jul;38(7):3652-3673.PMID:34091867DOI:10.1007/s12325-021-01797-5.
Schizophrenia is characterized by positive, negative, cognitive, and affective symptoms. Antipsychotic medications, which work by blocking the dopamine D2 receptor, are the foundation of pharmacotherapy for schizophrenia to control positive symptoms. Cariprazine is a dopamine D3 receptor-preferring D3/D2 partial agonist antipsychotic that is approved for the treatment of schizophrenia (USA and European Union [EU]) and manic and depressive episodes associated with bipolar I disorder (USA). Partial agonist agents have a lower intrinsic activity at receptors than full agonists, so they act as either functional agonists or functional antagonists depending on the surrounding neurotransmitter environment. Beyond efficacy against positive symptoms, the unique D3-preferring partial agonist pharmacology of Cariprazine suggests potential advantages against negative symptoms, and cognitive and functional impairment, which are challenging to treat. The efficacy and safety of Cariprazine in adult patients with schizophrenia have been demonstrated in four short-term randomized, double-blind, placebo-controlled clinical trials, two long-term open-label studies, one relapse prevention study, and one prospective negative symptom study versus the active comparator risperidone. Additional post hoc investigations have supported efficacy across individual symptoms and domains in schizophrenia, as well as in diverse areas of interest including cognition, functioning, negative symptoms, hostility, and global well-being. This comprehensive review of Cariprazine summarizes its pharmacologic profile, clinical trial evidence, and post hoc investigations. Collective evidence suggests that the pharmacology of Cariprazine may offer broad-spectrum efficacy advantages for patients with schizophrenia, including effects against difficult-to-treat negative and cognitive symptoms, as well as functional improvements. Cariprazine was generally safe and well tolerated in patients with short- and long-term exposure and no new safety concerns were associated with longer-duration treatment.Trial registration ClinicalTrials.gov identifiers, NCT00404573, NCT00694707, NCT01104766, NCT01104779, NCT01412060, NCT00839852, NCT01104792.