Cariprazine (RGH-188), a Dopamine D₃ Receptor-Preferring, D₃/D₂ Dopamine Receptor Antagonist–Partial Agonist Antipsychotic Candidate: In Vitro and Neurochemical Profile

Abstract

receptors and potently antagonized R(ϩ)-2-dipropylamino-7-hydroxy-1,2,3,4-tetra-hydronaphtalene HBr (7-OH-DPAT)-induced suppression of cAMP formation (pK b 9.57). In these functional assays, cariprazine showed similar (D 2 ) or higher (D 3 ) antagonist-partial agonist affinity and greater (3-to 10-fold) D 3 versus D 2 selectivity compared with aripiprazole. In in vivo turnover and biosynthesis experiments, cariprazine demonstrated D 2 -related partial agonist and antagonist properties, depending on actual dopaminergic tone. The antagonist-partial agonist properties of cariprazine at D 3 and D 2 receptors, with very high and preferential affinity to D 3 receptors, make it a candidate antipsychotic with a unique pharmacological profile among known antipsychotics. Dopamine D 3 receptors, cloned in the beginning of the 1990s (Sokoloff et al., 1990), are most abundant in the mesolimbic regions (i.e., nucleus accumbens, island of Calleja) where dysregulation of neurotransmission is thought to be associated with psychosis. The discovery that most antipsychotics, in addition to binding to D 2 receptors, display reasonably high affinity for D 3 receptors, led to the assumption that these receptors may also be responsible for antipsychotic efficacy (Sokoloff et al., 1995). Unfortunately, the selective D 3Article, publication date, and citation information can be found at

Cariprazine in Bipolar Disorder: Clinical Efficacy, Tolerability, and Place in Therapy

“…Table 1 In vitro binding a nities for cariprazine in human receptors [24] Although the pharmacokinetics of cariprazine in subjects with bipolar disorder is not known, the pharmacokinetics of cariprazine was tested in small short-term studies in both healthy volunteers and in subjects with schizophrenia, with similar results [25].…”

Mice Lacking the Serotonin Htr2B Receptor Gene Present an Antipsychotic-Sensitive Schizophrenic-Like Phenotype

“…The two main classes are known as typical and atypical antipsychotics. Response to dizocilpine ↑ Figure 1d Response to amphetamine ↑ Figure 1e Sensorimotor gating Prepulse inhibition ↓ Figure 1a and b Attention Latent Inhibition X Figure 2e Cognitive function Novel object recognition memory (short term) ↓ Figure 2a Novel object recognition memory (long term) ↓ Figure 2b Contextual fear memory ↓ Figure 2c Cued fear memory ↓ Figure 2d Social memory ↓ Figure 1h Social interaction Sociability ↓ Figure 1f Juvenile conspecific ↓ Supplementary Figure S1f Sleep architecture Wakefulness ↑ Figure 3a and c NREM sleep ↓ Figure 3a and d REM sleep - Figure 3a and e REM latency ↓ Figure 3b for 5-HT 2B receptors (eg, aripiprazole, cariprazine) (Kiss et al, 2010;Shapiro et al, 2003). Notably, it was recently shown that the efficacy of clozapine, but not haloperidol, is diminished in Pet1 −/− mice that lack 5-HT neurons, and thus depends on an intact presynaptic serotonergic system (Yadav et al, 2011).…”

“…Indeed, atypical antipsychotics, of which clozapine is the prototype, consist of agents that are more potent antagonists of serotonin 2A (5-HT 2A ) receptors over D 2 receptors (Gonzalez-Maeso et al, 2008). Many atypical antipsychotics show similar affinity for 5-HT 2B and 5-HT 2A receptors (eg, clozapine, amisulpride, asenapine, aripiprazole, or cariprazine) (Abbas et al, 2009;Kiss et al, 2010;Shahid et al, 2009;Shapiro et al, 2003), although the contribution of the 5-HT 2B receptor to the action of antipsychotic compounds has never been reported. Notably, the elucidation of the intricate mechanisms underlying the neurobiology of schizophrenia is imperative in order to develop novel drugs with improved therapeutic efficacy (Kvajo et al, 2012).…”

Pharmacological Treatment of Schizophrenia:

“…Cariprazine shows partial agonism at D 2 /D 3 receptors, with preferential binding to D 3 receptors, and partial agonism at 5-HT 1A receptors [29,30]. Compared with aripiprazole, cariprazine showed lower affinity for D 2 and higher affinity for D 3 receptors [30]. The dopamine D 3 receptor is thought to play roles in the regulation of cognitive and emotional functions [31].…”

“…Akathisia was less frequently observed in the brexpiprazole groups (4.2-6.5%) than in the placebo group (7.1%). Cariprazine shows partial agonism at D 2 /D 3 receptors, with preferential binding to D 3 receptors, and partial agonism at 5-HT 1A receptors [29,30]. Compared with aripiprazole, cariprazine showed lower affinity for D 2 and higher affinity for D 3 receptors [30].…”