Cariprazine

Cariprazine

Systematic (IUPAC) name
N​ '-[trans-4-[2-[4-(2,3-dichlorophenyl)-1-piperazinyl]ethyl]cyclohexyl]-N,N-dimethylurea
Clinical data
Trade names	Vraylar
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	High
Protein binding	91–97%
Metabolism	Hepatic via CYP3A4 & to a lesser extent, CYP2D6
Biological half-life	2–5 days (2–3 wks for active metabolite, desmethylcariprazine)
Excretion	urine (21%), bile
Identifiers
CAS Number	839712-12-8
ATC code	N05AX15 (WHO)
PubChem	CID: 11154555
IUPHAR/BPS	7671
DrugBank	DB06016 Y
ChemSpider	25999972 Y
KEGG	D09997 Y
ChEBI	CHEBI:90933 Y
ChEMBL	CHEMBL2028019
Chemical data
Formula	C21H32Cl2N4O
Molecular mass	427.411 g/mol
SMILES CN(C)C(=O)N[C@H]1CC[C@H](CCN2CCN(CC2)c2cccc(Cl)c2Cl)CC1
InChI InChI=1S/C21H32Cl2N4O/c1-25(2)21(28)24-17-8-6-16(7-9-17)10-11-26-12-14-27(15-13-26)19-5-3-4-18(22)20(19)23/h3-5,16-17H,6-15H2,1-2H3,(H,24,28)/t16-,17- Y Key:KPWSJANDNDDRMB-QAQDUYKDSA-N Y

Mechanism of cariprazine action as antagonist or agonist.

Cariprazine (trade name Vraylar, previously known as RGH-188) is an antipsychotic drug developed by Gedeon Richter. It acts as a D₂ and D₃ receptor partial agonist, with high selectivity towards the D₃ receptor. Positive Phase III study results were published for schizophrenia and mania in early 2012, and for bipolar disorder I depression from a Phase II trial in 2015. Action on the dopaminergic systems makes it also potentially useful as an add-on therapy in major depressive disorder

Rights are currently owned by Gedeon Richter and Actavis. The drug received FDA approval on September 17, 2015.

Medical uses

Cariprazine is approved for schizophrenia and bipolar disorder. It has also been investigated as a potential adjunct in treatment-resistant major depressive disorder.

Side effects

The most prevalent side effects for cariprazine include akathisia, insomnia, and weight gain. Cariprazine does not appear to impact metabolic variables or prolactin levels, and unlike many other antipsychotics, does not increase the electrocardiogram (ECG) QT interval. In short term clinical trials extrapyramidal effects, sedation, akathisia, nausea, dizziness, vomiting, anxiety, and constipation were observed. One review characterized the frequency of these events as "not greatly different from that seen in patient treated with placebo" but a second called the incidence of movement-related disorders "rather high".

Regarding side effects, the label of Cariprazine states, "The possibility of lenticular changes or cataracts cannot be excluded at this time."

Pharmacodynamics

Unlike many antipsychotics that are D₂ and 5-HT_2A receptor antagonists, cariprazine is a D₂ and D₃ partial agonist. It also has a higher affinity for D₃ receptors. The D₂ and D₃ receptors are important targets for the treatment of schizophrenia, because the overstimulation of dopamine receptors has been implicated as a possible cause of schizophrenia. Cariprazine acts to inhibit overstimulated dopamine receptors (acting as an antagonist) and stimulate the same receptors when the endogenous dopamine levels are low. Cariprazine’s high selectivity towards D₃ receptors could prove to reduce side effects associated with the other antipsychotic drugs, because D₃ receptors are mainly located in the ventral striatum and would not incur the same motor side effects (extrapyramidal symptoms) as drugs that act on dorsal striatum dopamine receptors. Cariprazine also acts on 5-HT_1A receptors, though the affinity is considerably lower than the affinity to dopamine receptors (seen in monkey and rat brain studies). In the same studies, cariprazine has been noted to produce pro-cognitive effects, the mechanisms of which are currently under investigation. An example of pro-cognitive effects occurred in pre-clinical trials with rats: rats with cariprazine performed better in a scopolamine-induced learning impairment paradigm in a water labyrinth test. This may be due to the selective antagonist nature of D₃ receptors, though further studies need to be conducted. This result could be very useful for schizophrenia, as one of the symptoms includes cognitive deficits.

Cariprazine has partial agonist as well as antagonist properties depending on the endogenous dopamine levels. When endogenous dopamine levels are high (as is hypothesized in schizophrenic patients), cariprazine acts as an antagonist by blocking dopamine receptors. When endogenous dopamine levels are low, cariprazine acts more as an agonist, increasing dopamine receptor activity. In monkey studies, the administration of increasing does of cariprazine resulted in a dose-dependent and saturable reduction of specific binding. At the highest dose (300 μg/kg), the D₂/D₃ receptors were 94% occupied, while at the lowest dose (1 μg/kg), receptors were 5% occupied.

Receptor	Ki (nM)	Pharmacodynamic action
5-HT1A	3	Partial agonism
5-HT2A	19	Inverse agonism
5-HT2B	0.58	Inverse agonism
5-HT2C	134	Inverse agonism
5-HT7	111	Antagonism
D2L	0.49	Partial agonism
D2S	0.69	Partial agonism
D3	0.085	Partial agonism
H1	23	Inverse agonism

Pharmacokinetics

Cariprazine has high oral bioavailability and can cross the blood brain barrier easily in humans because it is lipophilic. In rats, the oral bioavailability was 52% (with a dose of 1 mg/kg).

See also

• Aripiprazole
• Brexpiprazole
• ITI-007
• RP5063
• Bifeprunox
• Lurasidone