Cariprazine-hydrochloride-RGH188-hydrochloride-DataSheet-MedChemExpress

1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemECariprazine hydrochlorideCat. No.: HY-14763ACAS No.: 1083076-69-0Synonyms: RGH188 hydrochloride分式: CHClNO分量: 463.87作靶點(diǎn): Dopamine Receptor; 5-HT Receptor作通路: GPCR/G Protein; Neuronal Signaling儲存式: Powder -20C 3 years4C 2 yearsIn

2、solvent -80C 6 months-20C 1 month溶解性數(shù)據(jù)體外實(shí)驗(yàn) DMSO : 6.67 mg/mL (14.38 mM; Need ultrasonic)Mass Solvent1 mg 5 mg 10 mg Concentration制備儲備液1 mM 2.1558 mL 10.7789 mL 21.5578 mL5 mM 0.4312 mL 2.1558 mL 4.3116 mL10 mM 0.2156 mL 1.0779 mL 2.1558 mL請根據(jù)產(chǎn)品在不同溶劑中的溶解度，選擇合適的溶劑配制儲備液，并請注意儲備液的保存式和期限。體內(nèi)實(shí)驗(yàn)請根據(jù)您的實(shí)驗(yàn)動物和給藥式

3、選擇適當(dāng)?shù)娜芙獍福渲魄罢埾扰渲瞥吻宓膬湟?，再依次添加助溶?為保證實(shí)驗(yàn)結(jié)果的可靠性，體內(nèi)實(shí)驗(yàn)的作液，建議您現(xiàn)現(xiàn)配，當(dāng)天使；澄清的儲備液可以根據(jù)儲存條件，適當(dāng)保存；以下溶劑前的百分 指該溶劑在您配制終溶液中的體積占)：1. 請依序添加每種溶劑： 10% DMSO 40% PEG300 5% Tween-80 45% salineSolubility: 0.67 mg/mL (1.44 mM); Clear solution2. 請依序添加每種溶劑： 10% DMSO 90% (20% SBE-CD in saline)Solubility: 0.67 mg/mL (1.44 mM); Cle

4、ar solution3. 請依序添加每種溶劑： 10% DMSO 90% corn oil1/4 Master of Small Molecules 您邊的抑制劑師www.MedChemESolubility: 0.67 mg/mL (1.44 mM); Clear solutionBIOLOGICAL ACTIVITY物活性 Cariprazine(RGH188)鹽酸鹽有抗精神病活性，對D3和D2受體有較親和，Ki分別為0.09 nM和0.5 nM，對5-HT(1A)受體有定親和。IC50 & Target Ki: 0.49 nM (D2 receptor), 0.085 nM (D3 r

5、eceptor), 2.6 nM (5-HT1A receptor) 1體外研究 Cariprazine stimulates inositol phosphate (IP) formation with a high potency (pEC50 8.5) with relatively lowefficacy (Emax 30%) 2. Cariprazine, a novel candidate antipsychotic, demonstrated approximately 10-foldhigher affinity for human D3 versus human D2L an

6、d 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) withpure antagonism. Cariprazine has lower affinity at human and rat hippocampal 5-HT1A receptors (pKi 8.59and 8.34, respectively) and demonstrate

7、s 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 and6.87, respectively) suggest Cariprazines reduced propensity for adverse events related to these receptors2. Cariprazine is ove

8、r sixfold more potent (EC50=1.4 nM) than Aripiprazole (EC50=9.2 nM) in inhibitingisoproterenol-induced cAMP production in HEK-293 cells 4.體內(nèi)研究 Administration of Cariprazine (30 g/kg) reduces the striatal uptake of both radioligands to the level ofnonspecific binding compared with baseline PET measur

9、ements. Cariprazine has negligible effect on thetime-activity curves in the cerebellum. At doses of 5.0 and 30 g/kg, Cariprazine causes a dose-dependentdopamine D2/D3 receptor occupancy of 45% and 80% for both antagonist 11C raclopride and agonistradioligand 11CMNPA. Receptor occupancy of dopamine D

10、2/D3 receptors calculated using the transientequilibrium and the MRTM2 methods ranged from 5% at the lowest dose (1.0 g/kg) to 94% at the highestdose (300 g/kg) 1. The effects of 5 doses of Cariprazine (ranging from 0.005 to 0.15 mg/kg) are examinedon EPM behavior of wild-type mice. Whereas lower do

11、ses of Cariprazine (0.005 to 0.02 mg/kg) do not alterthe time spent in open arms, the two higher doses (0.08 and 0.15 mg/kg) lead to a significant decline of thismeasure (ANOVA, (F(5,52)=4.20; p=0.0032). Moreover, the two higher doses of Cariprazine also lead to asignificant decrease in the total nu

12、mber of arm entries (F(5,52)=7.21; p=0.0001) but this decrease in thetotal number of arm entries is largely accounted for by a significant decrease in the number of closed armentries (F(5,52)=11.75; p=0.0001). The two highest doses of Cariprazine (0.08 and 0.15 mg/kg) havesignificant effects on loco

13、motor activity, but doses ranging from 0.005 to 0.02 mg/kg do not affect anxiety-likebehavior or locomotor activity in the EPM test 3. A significant (P 4.PROTOCOLKinase Assay 2 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 25

14、0 L) contain 50 M (striatum and hippocampus) or 1 M (D2 and D3 cellmembrane) GDP, the ligand to be examined, and membrane suspension (250 g tissue/tube for the striatumand hippocampus and 20 g protein/tube for hD2 and hD3 membranes). Samples are preincubated for 102/4 Master of Small Molecules 您邊的抑制

15、劑師www.MedChemEmin at 30C. After the addition of 50 pM 35SGTPS, membranes are incubated for an additional 60 min at30C. Nonspecific binding is determined in the presence of 10 M GTPS; basal binding is determined in thepresence of buffer only. The assay is terminated by rapid filtration through UniFil

16、ter GF/B using a harvester,and the membranes washed four times with 1 mL of ice-cold buffer. After drying (40C for 1 h), 40 L ofMicroscint is added to the filters, and the bound radioactivity is determined by a TopCount NXT counter 2.MCE has not independently confirmed the accuracy of these methods.

17、 They are for reference only.Cell Assay 2 Cells are seeded on a 24-well tissue culture plate in 500 L of medium. Fifty microliters of medium containing0.55 Ci myo-3Hinositol is added (final concentration 1 Ci/mL) and incubated for 18-20 h. Cells are thenwashed three times with buffer containing 140

18、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 (37C)in medium with test compounds alone (agonist test) or alongside 1000 nM ()-Quinpirole (antagonist test).Medium is then aspirated off, cells are lys

19、ed by adding 400 L of 0.1 M HCl/2 mM CaCl2, and supernatantsare frozen at 72C. After thawing and centrifugation at 1000g for 10 min, 200 L of each supernatant isloaded on 250 L of AG1-X8 (formate form) anion exchange column. Effluent is discarded, and columns arewashed twice in 1.5 mL of distilled w

20、ater. IPs are eluted with 2.5 mL of 1 M ammonium formate/0.1 M formicacid directly into scintillation vials, 10 mL of Optiphase HiSafe 3 is added, and the radioactivity is determinedin a TriCarb 4900 scintillation counter 2.MCE has not independently confirmed the accuracy of these methods. They are

21、for reference only.Animal Mice 3Administration 34 Experiments are performed on wild-type C57Bl/6J mice. In tests of cognitive functions, it is essential toemploy concentrations of drugs that have no effects on emotional behavior and that do not impair locomotoractivity. Whether Cariprazine (administ

22、ered at a dose range of 0.005 to 0.15 mg/kg) is first tested affected thebehavior of mice in the EPM, a test of anxiety-related behavior that is also critically dependent upon normallocomotor activity. Animals are exposed to an EPM apparatus designed for mice (leg height: 45 cm, armlength: 35 cm, la

23、ne width: 5 cm, wall height: 15 cm). Testing (under 100 lux lighting) is performed between 1and 4 PM. Mice are placed in the center of the maze and their time spent in open arms and the number ofclosed and open arm entries during a 5 min test period is recorded. Measures of the time spent in open ar

24、msand the number of open arm entries served as a measure of anxiety-like behavior. The number of closed armentries served as a measure of locomotor activity.Rats 4Adult male Sprague-Dawley rats (150-300 g) are used. Cariprazine is dissolved in 0.9% saline andadministered at 0.06, 0.25, 0.5, and 1.0

25、mg/kg via intraperitoneal (i.p.) injection 1 h before i.c.v. injection ofouabain 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).MCE has not

26、independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. 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):579-83/4 Master of Small Molecules 您邊的抑制劑師www.MedChemE2. Kiss B, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonis