1、Hotline: 400-820-3792Inhibitors Agonists Screening Librarieswww.MedChemECariprazineCat. No.: HY-14763CAS No.: 839712-12-8Synonyms: RGH-188分式: CHClNO分量: 427.41作靶點: Dopamine Receptor; 5-HT Receptor作通路: GPCR/G Protein; Neuronal Signaling儲存式: Powder -20C 3 years4C 2 yearsIn solvent -80C 6 months-20C 1 m

2、onthBIOLOGICAL ACTIVITY物活性 Cariprazine種新型抗精神病候選藥物，結(jié)合D3, D2 和 5-HT1A 的 Ki 為0.085 nM，0.49 nM，2.6 nM。IC50 & Target Ki: 0.49 nM (D2 receptor), 0.085 nM (D3 receptor), 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 l

3、owefficacy (Emax 30%) 2. Cariprazine, a novel candidate antipsychotic, demonstrated approximately 10-foldhigher 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

4、 9.24) withpure antagonism. Cariprazine has lower affinity at human and rat hippocampal 5-HT1A receptors (pKi 8.59and 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-H

5、T2C receptors (pKi 7.63 and6.87, respectively) suggest Cariprazines reduced propensity for adverse events related to these receptors2. Cariprazine is over 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Admin

6、istration of Cariprazine (30 g/kg) reduces the striatal uptake of both radioligands to the level ofnonspecific binding compared with baseline PET measurements. Cariprazine has negligible effect on thetime-activity curves in the cerebellum. At doses of 5.0 and 30 g/kg, Cariprazine causes a dose-depen

7、dentdopamine D2/D3 receptor occupancy of 45% and 80% for both antagonist 11C raclopride and agonist1/3 Master of Small Molecules 您邊的抑制劑師www.MedChemEradioligand 11CMNPA. Receptor occupancy of dopamine D2/D3 receptors calculated using the transientequilibrium and the MRTM2 methods ranged from 5% at th

8、e 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 doses of Cariprazine (0.005 to 0.02 mg/kg) do not alterthe time spent in open arms, the two higher do

9、ses (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 number of arm entries (F(5,52)=7.21; p=0.0001) but this decrease in thetotal number of arm entries is

10、 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 locomotor activity, but doses ranging from 0.005 to 0.02 mg/kg do not affect anxiety-likebehavior or lo

11、comotor 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 250 L) contain 50 M (striatum and hippocampus) or 1 M (D2 and D3 cellmembrane) GDP, the ligand to be

12、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 10min at 30C. After the addition of 50 pM 35SGTPS, membranes are incubated for an additional 60 min at30C. Nonspecific binding is determ

13、ined in the presence of 10 M GTPS; basal binding is determined in thepresence 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 (40C for 1 h), 40 L ofMicroscint is added

14、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. 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 contain

15、ing0.55 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 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

16、(37C)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 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 s

17、upernatant 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 water. 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, a

18、nd the radioactivity is determinedin a TriCarb 4900 scintillation counter 2.MCE has not independently confirmed the accuracy of these methods. They are for reference only.Animal Mice 3Administration 34 Experiments are performed on wild-type C57Bl/6J mice. In tests of cognitive functions, it is essen

19、tial toemploy concentrations of drugs that have no effects on emotional behavior and that do not impair locomotoractivity. Whether Cariprazine (administered 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 als

20、o critically dependent upon normal2/3 Master of Small Molecules 您邊的抑制劑師www.MedChemElocomotor activity. Animals are exposed to an EPM apparatus designed for mice (leg height: 45 cm, armlength: 35 cm, lane width: 5 cm, wall height: 15 cm). Testing (under 100 lux lighting) is performed between 1and 4 P

21、M. 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 armsand the number of open arm entries served as a measure of anxiety-like behavior. The number of cl

22、osed 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 mg/kg via intraperitoneal (i.p.) injection 1 h before i.c.v. injection ofouabain and daily thereaft

23、er 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 independently confirmed the accuracy of these methods. They are for reference only.REFERENCES1. Sen

24、eca 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):579-82. Kiss B, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-prefe