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RGH-188 is an orally active, potent dopamine D3/D2 receptor antagonist/partial agonist atypical antipsychotic for the treatment of schizophrenia and bipolar mania.
RGH-188 displayed high affinity to human D3 receptors (Ki: 0.085 nM) and approximately six- and thirty-times less affinity to human D2, and 5-HT1A receptors. In various in vitro and in vivo assays RGH-188 behaved either as an antagonist or as a partial agonist on dopamine D3 and D2 receptors.
RGH-188 displayed potent antipsychotic activity (0.1-0.8 mg/kg) in rodent models such as apomorphine-induced climbing, amphetamine- and phencyclidine-induced hypermotility, conditioned avoidance response. It significantly improved the learning performance of rats (0.02-0.2 mg/kg) impaired by scopolamine in a water-labyrinth learning paradigm. RGH-188 showed no EPS liability as it produced no catalepsy up to 100-fold therapeutic range.
In a nonhuman primate positron emission tomography (PET) study using 11C-raclopride RGH-188 occupied striatal D2/D3 receptors in a dose dependent and saturable manner with an ED50 of 7 μg/kg iv. In healthy male subjects multiple administration of 1 mg RGH-188 resulted in over 70% D2/D3 receptor occupancy and the displacement showed correlation with RGH-188 and metabolites plasma levels.
After single administration to healthy volunteers, Tmax for RGH-188 was 3-4 hours and the terminal disposition half-life was 5-6 days. Over the dose range of 0.5-2.5 mg AUC of the parent drug was approximately dose-proportional. Systemic exposure to the pharmacologically active metabolites, desmethyl- and didesmethyl-RGH-188 was 20-30% and 50-200% of that to the parent, respectively.
There is a marked overlap between the neuronal pathways involved in sleep/wake regulation and depression. Both the structure and the organization of sleep are altered in depressed patients; they enter the rapid eye movement (REM) sleep earlier, the amount of REM is increased and also the non-REM sleep is reduced in the first sleep cycle.
Serotonin reuptake inhibitor antidepressants (SSRIs) exert their therapeutic effect on the serotonergic system, which has a central role in the modulation of mood and vigilance.
The aim of this study was to investigate the acute and long-term effect of the SSRI escitalopram on REM sleep in rats.
The effect of a single (10 mg/kg i.p.) and chronically administered (10 mg/kg/day, released by an osmotic mini pump for 21-day-long) escitalopram was studied in male Wistar rats. Electroencephalogram, electromyogram and motility were recorded for three hours starting at light onset.
The acutely administered escitalopram significantly reduced the time spent in REM sleep in the first three hours, compared to control. However, this REM-reducing effect was abolished after chronic administration.
There was a clear difference in the effect of escitalopram on REM sleep following acute and chronic administration, providing evidence for the adaptive changes of serotonin receptors, which take several weeks to evolve, and considered to have a role in the development of therapeutic effect of SSRIs in the treatment of depression. This study was supported by the TAMOP-2.2.1. B-09/1/KMR-2010-0001 and by Richter Gedeon Plc.
Schizophrenia is a multifactorial disease requiring treatment that manages a broad spectrum of symptoms. Cariprazine is a dopamine D3 and D2 receptor partial agonist antipsychotic candidate with preferential D3 receptor binding.
Evaluate the pharmacological/behavioral profile of cariprazine in animal models.
To determine the activity and receptor occupancy of cariprazine in rat models at doses that confer antipsychotic-like efficacy.
Cariprazine was evaluated in rat paradigms that model symptoms of schizophrenia, mania, and depression. Occupancy of cariprazine, aripiprazole, and risperidone at D3 and D2 receptors was also compared.
Cariprazine showed antipsychotic-like efficacy on conditioned avoidance response and amphetamine-induced motor activity tests (ED50: 0.8 and 0.1 mg/kg) with potencies similar to risperidone (ED50: 0.9 and 0.2 mg/kg) and greater than aripiprazole (ED50: 18 and 3.9 mg/kg). While all 3 compounds displayed high in vivo occupancy of D2 receptors, only cariprazine displayed potent in vivo occupancy of D3 receptors at antipsychotic-like doses (ED50 [% inhibition]: cariprazine, 0.43 mg/kg [99.3]; aripiprazole, >30 mg/kg [26.4]; risperidone: ~2.3 mg/kg [53.4]). At or below antipsychotic-like doses, cariprazine demonstrated antimanic-like, antidepressant-like, anxiolytic-like, and procognitive effects in rats. As determined using D3 receptor knockout mice, procognitive and antidepressant-like effects of cariprazine were shown to be mediated via the D3 receptor.
At antipsychotic-like effective doses in rats, cariprazine demonstrated balanced and significant occupancy at both dopamine D2 and D3 receptors; other antipsychotics displayed relatively low D3 receptor occupancy. Additionally, at antipsychotic-like doses cariprazine demonstrated efficacy in different rat models of mania, mood, anxiety, and cognition.
This study examined the chronic effects of aripiprazole and cariprazine on serotonin (5-HT1A and 5-HT2A) and glutamate (NMDA and AMPA) receptor subtypes. In addition, the effects of aripiprazole on D2 and D3 receptors were tested and compared with previously reported cariprazine data.
Rats received vehicle, aripiprazole (2, 5, or 15 mg/kg), or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Receptor levels were quantified using autoradiographic assays on brain sections from the medial prefrontal cortex (MPC), dorsolateral frontal cortex (DFC), nucleus accumbens (NAc), caudate-putamen medial (CPu–M), caudate-putamen lateral (CPu–L), hippocampal CA1 (HIPP–CA1) and CA3 (HIPP–CA3) regions, and the entorhinal cortex (EC).
Similar to previous findings with cariprazine, aripiprazole upregulated D2 receptor levels in various regions; D3 receptor changes were less than those reported with cariprazine. All aripiprazole doses and higher cariprazine doses increased 5-HT1A receptors in the MPC and DFC. Higher aripiprazole and all cariprazine doses increased 5-HT1A receptors in HIPP–CA1 and HIPP–CA3. Aripiprazole decreased 5-HT2A receptors in the MPC, DFC, HIPP–CA1, and HIPP–CA3 regions. Both compounds decreased NMDA receptors and increased AMPA receptors in select brain regions.
Long-term administration of aripiprazole and cariprazine had similar effects on 5-HT1A, NMDA, and AMPA receptors. However, cariprazine more profoundly increased D3 receptors while aripiprazole selectively reduced 5-HT2A receptors. These results suggest that the unique actions of cariprazine on dopamine D3 receptors, combined with its effects on serotonin and glutamate receptor subtypes, may confer the clinical benefits, safety, and tolerability of this novel compound in schizophrenia and bipolar mania.
All clinically effective antipsychotics are known to act on the dopaminergic system, and previous studies have demonstrated that repeated treatment with antipsychotics produced region-specific changes in dopamine receptor levels. Cariprazine is a dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. We examined the effects of chronic cariprazine administration on dopamine receptor levels.
Rats were administered either vehicle or cariprazine (0.06, 0.2, or 0.6 mg/kg) for 28 days. Dopamine receptor levels were quantitated using autoradiographic assays on brain tissue sections from the medial prefrontal cortex (mPFC), nucleus accumbens (NAc), caudate putamen (CPu), hippocampus (HIPP), olfactory tubercle (OT), and islands of Calleja (ICj).
Chronic treatment with cariprazine did not alter D1 receptor levels in any brain region tested. Cariprazine increased D2 receptor levels in mPFC (27%–43%), NAc (40%–45%), medial (41%–53%) and lateral (52%–63%) CPu, and HIPP (38%). Cariprazine dose-dependently upregulated D3 receptor levels in ICj (32%–57%), OT (27%–67%), and NAc shell (31%–48%). Repeated cariprazine treatment increased D4 receptor in NAc (53%–82%), medial (54%–98%) and lateral (58%–74%) CPu, and HIPP (38%–98%).
Similar to other antipsychotics, cariprazine upregulated D2 and D4 receptor levels in various brain regions. Cariprazine was unique among antipsychotics in increasing D3 receptor levels, which may support its unique psychopharmacologic properties.
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