Cariprazine is a novel antipsychotic drug candidate that exhibits high affinity for theD₃(K_i=0.085 nM) andD₂(K_i=0.49 nM) receptors, and moderate affinity for the5-HT_1Areceptor (K_i=2.6 nM).

Cariprazine stimulates inositol phosphate (IP) formation with a high potency (pEC₅₀8.5) with relatively low efficacy (E_max30%)^[2]. Cariprazine, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D₃versus human D_2Land human D_2Sreceptors (pK_i10.07, 9.16, and 9.31, respectively). Cariprazine displays high affinity at human serotonin (5-HT) type 2B receptors (pK_i9.24) with pure antagonism. Cariprazine has lower affinity at human and rat hippocampal 5-HT_1Areceptors (pK_i8.59 and 8.34, respectively) and demonstrates low intrinsic efficacy. Cariprazine displays low affinity at human 5-HT_2Areceptors (pK_i7.73). Moderate or low affinity for histamine H₁and 5-HT_2Creceptors (pK_i7.63 and 6.87, respectively) suggest Cariprazine's 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].

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/D₃receptor occupancy of ~45% and ~80% for both antagonist [¹¹C] raclopride and agonist radioligand [¹¹C]MNPA. Receptor occupancy of dopamine D₂/D₃receptors 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<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)^[4].

427.41

Solid

C₂₁H₃₂Cl₂N₄O

839712-12-8

卡利拉嗪

Room temperature in continental US; may vary elsewhere.

DMSO : 2 mg/mL(4.68 mM;ultrasonic and warming and heat to 60℃)

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