"目录号: HY-14763A
GPCR/G ProteinNeuronal Signaling-
Cariprazine(RGH188)盐酸盐有抗精神病活性，对D3和D2受体有较高亲和力，Ki分别为0.09 nM和0.5 nM，对5-HT(1A)受体有一定亲和力。
Dopamine Receptor5-HT Receptor
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生物活性
Description
Cariprazine hydrochloride is a novel antipsychotic drug candidate that exhibits high affinity for theD3(Ki=0.085 nM) andD2(Ki=0.49 nM) receptors, and moderate affinity for the5-HT1Areceptor (Ki=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 (pEC508.5) with relatively low efficacy (Emax30%)[2]. Cariprazine, a novel candidate antipsychotic, demonstrated approximately 10-fold higher affinity for human D3versus human D2Land human D2Sreceptors (pKi10.07, 9.16, and 9.31, respectively). Cariprazine displays high affinity at human serotonin (5-HT) type 2B receptors (pKi9.24) with pure antagonism. Cariprazine has lower affinity at human and rat hippocampal 5-HT1Areceptors (pKi8.59 and 8.34, respectively) and demonstrates low intrinsic efficacy. Cariprazine displays low affinity at human 5-HT2Areceptors (pKi7.73). Moderate or low affinity for histamine H1and 5-HT2Creceptors (pKi7.63 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/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].
Clinical Trial
NCT01838876
Forest Laboratories-Gedeon Richter Ltd.
Major Depressive Disorder
May 2013
Phase 3
NCT01104792
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
April 2010
Phase 3
NCT02670551
Forest Laboratories, LLC, an Allergan Affiliate-Forest Laboratories
Bipolar Disorder-Depression
March 2016
Phase 3
NCT02670538
Forest Laboratories
Bipolar Disorder-Depression
March 2016
Phase 3
NCT01058096
Forest Laboratories-Gedeon Richter Ltd.
Bipolar Disorder-Mania
February 2010
Phase 3
NCT01059539
Forest Laboratories-Gedeon Richter Ltd.
Bipolar I Disorder
January 2010
Phase 3
NCT01715805
Forest Laboratories-Gedeon Richter Ltd.
Major Depressive Disorder
November 2012
Phase 3
NCT01058668
Forest Laboratories-Gedeon Richter Ltd.
Mania-Bipolar I Disorder
February 2010
Phase 3
NCT01396447
Forest Laboratories-Gedeon Richter Ltd.
Depression, Bipolar
July 2011
Phase 2
NCT00839852
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
May 2009
Phase 2
NCT01412060
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
August 2011
Phase 3
NCT01469377
Forest Laboratories-Gedeon Richter Ltd.
Major Depressive Disorder
December 2011
Phase 2
NCT00852202
Forest Laboratories-Gedeon Richter Ltd.
Bipolar Depression
June 2009
Phase 2
NCT01104779
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
April 2010
Phase 3
NCT02165098
Gedeon Richter Plc.
Pharmacokinetic Profile
June 2014
Phase 1
NCT01376076
Forest Laboratories
Schizophrenia
June 2011
Phase 1
NCT01104766
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
April 2010
Phase 3
NCT00854100
Forest Laboratories-Gedeon Richter Ltd.
Major Depressive Disorder
June 2009
Phase 2
NCT00488618
Forest Laboratories-Gedeon Richter Ltd.
Bipolar Disorder
June 2007
Phase 2
NCT00862992
Mitsubishi Tanabe Pharma Corporation
Schizophrenia
April 2008
Phase 2
NCT01838876
Forest Laboratories-Gedeon Richter Ltd.
Major Depressive Disorder
May 2013
Phase 3
NCT01104792
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
April 2010
Phase 3
NCT02670551
Forest Laboratories, LLC, an Allergan Affiliate-Forest Laboratories
Bipolar Disorder-Depression
March 2016
Phase 3
NCT02670538
Forest Laboratories
Bipolar Disorder-Depression
March 2016
Phase 3
NCT01058096
Forest Laboratories-Gedeon Richter Ltd.
Bipolar Disorder-Mania
February 2010
Phase 3
NCT01059539
Forest Laboratories-Gedeon Richter Ltd.
Bipolar I Disorder
January 2010
Phase 3
NCT01715805
Forest Laboratories-Gedeon Richter Ltd.
Major Depressive Disorder
November 2012
Phase 3
NCT01058668
Forest Laboratories-Gedeon Richter Ltd.
Mania-Bipolar I Disorder
February 2010
Phase 3
NCT01396447
Forest Laboratories-Gedeon Richter Ltd.
Depression, Bipolar
July 2011
Phase 2
NCT00839852
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
May 2009
Phase 2
NCT01412060
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
August 2011
Phase 3
NCT01469377
Forest Laboratories-Gedeon Richter Ltd.
Major Depressive Disorder
December 2011
Phase 2
NCT00852202
Forest Laboratories-Gedeon Richter Ltd.
Bipolar Depression
June 2009
Phase 2
NCT01104779
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
April 2010
Phase 3
NCT02165098
Gedeon Richter Plc.
Pharmacokinetic Profile
June 2014
Phase 1
NCT01376076
Forest Laboratories
Schizophrenia
June 2011
Phase 1
NCT01104766
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
April 2010
Phase 3
NCT00854100
Forest Laboratories-Gedeon Richter Ltd.
Major Depressive Disorder
June 2009
Phase 2
NCT00488618
Forest Laboratories-Gedeon Richter Ltd.
Bipolar Disorder
June 2007
Phase 2
NCT00862992
Mitsubishi Tanabe Pharma Corporation
Schizophrenia
April 2008
Phase 2
NCT00404573
Forest Laboratories
Schizophrenia
November 2006
Phase 2
NCT00694707
Forest Laboratories-Gedeon Richter Ltd.
Schizophrenia
June 2008
Phase 2
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References
[1].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. Psychopharma