Cariprazine hydrochloride is a novel antipsychotic agent candidate that exhibits high affinity for the D₃ (K_i=0.085 nM) and D₂ (K_i=0.49 nM) receptors, and moderate affinity for the 5-HT_1A receptor (K_i=2.6 nM).

Cariprazine stimulates inositol phosphate (IP) formation with a high potency (pEC₅₀ 8.5) with relatively low efficacy (E_max 30%). Cariprazine, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D₃ versus human D_2L and human D_2S receptors (pK_i 10.07, 9.16, and 9.31, respectively). Cariprazine displays high affinity at human serotonin (5-HT) type 2B receptors (pK_i 9.24) with pure antagonism. Cariprazine has lower affinity at human and rat hippocampal 5-HT_1A receptors (pK_i 8.59 and 8.34, respectively) and demonstrates low intrinsic efficacy. Cariprazine displays low affinity at human 5-HT_2A receptors (pK_i 7.73). Moderate or low affinity for histamine H₁ and 5-HT_2C receptors (pK_i 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^[4].

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

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)^[4].

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

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)^[4].

西域 has not independently confirmed the accuracy of these methods. They are for reference only.

• . 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  [Content Brief]

  . Kiss B, et al. Cariprazine (RGH-188), a dopamine D(3) receptor-preferring, D(3)/D(2) dopamine receptor antagonist-partial agonist antipsychotic candidate: in vitro and neurochemical profile. J Pharmacol Exp Ther. 2010 Apr;333(1):328-40.  [Content Brief]

  . Zimnisky R, et al. Cariprazine, a dopamine D(3)-receptor-preferring partial agonist, blocks phencyclidine-induced impairments of working memory, attention set-shifting, and recognition memory in the mouse. Psychopharmacology (Berl). 2013 Mar;226(1):91-100.  [Content Brief]

  [4]. Gao Y, et al. Cariprazine exerts antimanic properties and interferes with dopamine D2 receptor β-arrestin interactions. Pharmacol Res Perspect. 2015 Feb;3(1):e00073.  [Content Brief]

  [5]. Citrome L. Cariprazine in schizophrenia: clinical efficacy, tolerability, and place in therapy. Adv Ther. 2013 Feb;30(2):114-26.  [Content Brief]