tcsc1570 Cariprazine (hydrochloride)

Cariprazine hydrochloride is a novel antipsychotic drug 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).

















IC50 & Target: Ki: 0.49 nM (D2 receptor), 0.085 nM (D3 receptor), 2.6 nM (5-HT1A receptor)^[1]

In Vitro: Cariprazine stimulates inositol phosphate (IP) formation with a high potency (pEC₅₀ 8.5) with relatively low efficacy (E_max 30%)^[2]. 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^[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].

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)^[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].