RESEARCH MONOGRAPH · KDC-MN-236
Cariprazine
Cariprazine (Vraylar) is a Hungarian-developed dopamine D2/D3 partial agonist from Gedeon Richter and AbbVie, approved by the FDA in 2015. It is structurally and mechanistically related to aripiprazole, but with a meaningful refinement: it preferentially binds the D3 receptor over D2 by roughly 6-fold. D3 receptors are concentrated in brain regions involved in motivation and cognition, which gives cariprazine a unique profile useful for the negative symptoms of schizophrenia (apathy, social withdrawal, cognitive blunting) where most antipsychotics fail. It is approved for schizophrenia, bipolar mania, bipolar depression, and as add-on for major depression. The very long half-lives of its active metabolites mean it takes weeks to reach steady state and weeks to wash out. Not stocked by Kodiac. This monograph is provided for research and educational reference.
Intrigue 0–100 blends mechanism novelty, evidence strength, and translational potential. Kodiac editorial, not peer-reviewed.
D3-preferring D2/D3 partial agonist
A piperazine partial agonist with D3 selectivity over D2 and 5-HT1A partial agonism; approved for schizophrenia and bipolar depression.
Abstract
Cariprazine ((1R,4R)-N-{4-[2-(4-(2,3-dichlorophenyl)piperazin-1-yl)ethyl]cyclohexyl}-N',N'-dimethylurea; CAS 839712-12-8; molecular formula C21H32Cl2N4O; molecular weight 427.41) is a piperazine D2/D3 partial agonist developed at Gedeon Richter (Hungary) and AbbVie, approved by the FDA in 2015 under the trade name Vraylar. Distinct among atypical antipsychotics for D3 preference: D3 affinity (Ki approximately 0.085 nM) exceeds D2 (Ki approximately 0.49 nM) by approximately 6-fold, the only clinical antipsychotic with D3-preferring activity. The D3 receptor is concentrated in mesolimbic and mesocortical regions associated with motivation, reward, and cognition; D3 partial agonism is hypothesized to improve negative symptoms and cognitive deficits in schizophrenia. 5-HT1A partial agonism (Ki approximately 2.6 nM) and 5-HT2A antagonism complete the profile. Plasma half-life of the parent is approximately 1 to 3 days; the active metabolites desmethyl-cariprazine and didesmethyl-cariprazine extend effective duration to several weeks. Metabolism is via CYP3A4. Approved for schizophrenia, bipolar mania, and bipolar depression; investigated for major depressive disorder adjunctive. Used as the reference D3-preferring partial agonist.
Mechanism of action
D3-preferring D2/D3 partial agonism (D3 approximately 6-fold higher affinity than D2). 5-HT1A partial agonism, 5-HT2A antagonism. Long-acting metabolites extend duration.
Reported research dose ranges
Clinical 1.5 to 6 mg per oral administration daily. Rodent studies 0.1 to 3 mg/kg/day.
References
- Kiss B, et al. Cariprazine (RGH-188), a dopamine D3 receptor-preferring, D3/D2 dopamine receptor antagonist-partial agonist antipsychotic candidate. J Pharmacol Exp Ther 2010.
- Citrome L. Cariprazine: chemistry, pharmacodynamics, pharmacokinetics, and metabolism, clinical efficacy, safety, and tolerability. Expert Opin Drug Metab Toxicol 2013.
- Earley W, et al. Efficacy of cariprazine on negative symptoms in patients with acute schizophrenia. Int J Neuropsychopharmacol 2019.
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FOR RESEARCH USE ONLY. Not for medical, diagnostic, or therapeutic purposes. Not for human consumption. All information is provided for research and educational purposes only.