Cariprazine

本公司产品仅用于科研实验，不得用于人体或动物的临床与诊断

Cariprazine 是一种新型抗精神病候选化合物，对 D3 (Ki=0.085 nM) 和 D2 (Ki=0.49 nM) 受体具有高亲和力，对 5-HT1A 受体具有中等亲和力 (Ki=2.6 nM)。

Cariprazine is a novel antipsychotic drug 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).(In Vitro):Cariprazine stimulates inositol phosphate (IP) formation with a high potency (pEC50 8.5) with relatively low efficacy (Emax 30%). 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 Cariprazine's reduced propensity for adverse events related to these receptors. 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. (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). 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. A significant (P<0.01) reduction in ouabain-induced hyperactivity is observed after acute i.p. administration of all doses of Cariprazine (mean±SEM: 0.06 mg/kg, 64.2±3.88; 0.25 mg/kg, 72.7±11.67; 0.5 mg/kg, 40.6±5.32; 1 mg/kg, 19.5±8.78) and lithium (40.4±12.78), compared with ouabain injection alone (114.6±14.33). The highest Cariprazine dose produced significant sedation (72% inhibition for Cariprazine 1.0 mg/kg aCSF vs. saline aCSF; P<0.05).

Cariprazine stimulates inositol phosphate (IP) formation with a high potency (pEC50 8.5) with relatively low efficacy (Emax 30%). 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 Cariprazine's reduced propensity for adverse events related to these receptors. 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.

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). 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. A significant (P<0.01) reduction in ouabain-induced hyperactivity is observed after acute i.p. administration of all doses of Cariprazine (mean±SEM: 0.06 mg/kg, 64.2±3.88; 0.25 mg/kg, 72.7±11.67; 0.5 mg/kg, 40.6±5.32; 1 mg/kg, 19.5±8.78) and lithium (40.4±12.78), compared with ouabain injection alone (114.6±14.33). The highest Cariprazine dose produced significant sedation (72% inhibition for Cariprazine 1.0 mg/kg aCSF vs. saline aCSF; P<0.05).

RGH-188

Cytoskeleton/Cell Adhesion Molecules

Akt

D3|D2|5-HT1A

Neurological Disease

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839712-12-8

427.41

C21H32Cl2N4O

>98% (HPLC)

In Vitro:?DMSO : 2 mg/mL (4.68 mM)

CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(CC2)c2cccc(Cl)c2Cl)CC1

——

(-20℃)

With Ice Pack

≥ 2 years