Dopamine D2 Receptor Partial Agonist Research Articles

Cariprazine for the Treatment of Schizophrenia: A Review of this Dopamine D3-Preferring D3/D2 Receptor Partial Agonist.

Cariprazine is an antipsychotic medication and received approval by the U.S. Food and Drug Administration for the treatment of schizophrenia in September 2015. Cariprazine is a dopamine D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors. The recommended dose range of cariprazine for the treatment of schizophrenia is 1.5-6 mg/d; the starting dose of 1.5 mg/d is potentially therapeutic. Cariprazine is administered once daily and is primarily metabolized in the liver through the CYP3A4 enzyme system and, to a lesser extent, by CYP2D6. There are two active metabolites of note, desmethyl-cariprazine and didesmethyl-cariprazine; the latter's half-life is substantially longer than that for cariprazine and systemic exposure to didesmethyl-cariprazine is several times higher than that for cariprazine. Three positive, 6-week, Phase 2/3, randomized controlled trials in acute schizophrenia demonstrated superiority of cariprazine over placebo. Pooled responder rates were 31% for cariprazine 1.5-6 mg/d vs. 21% for placebo, resulting in a number needed to treat (NNT) of 10. In a 26-72 week, randomized withdrawal study, significantly fewer patients relapsed in the cariprazine group compared with placebo (24.8% vs. 47.5%), resulting in an NNT of 5. The most commonly encountered adverse events (incidence ≥5% and at least twice the rate of placebo) are extrapyramidal symptoms (number needed to harm [NNH] 15 for cariprazine 1.5-3 mg/d vs. placebo and NNH 10 for 4.5-6 mg/d vs. placebo) and akathisia (NNH 20 for 1.5-3 mg/d vs. placebo and NNH 12 for 4.5-6 mg/d vs. placebo). Short-term weight gain appears small (approximately 8% of patients receiving cariprazine 1.5-6 mg/d gained ≥7% body weight from baseline, compared with 5% for those randomized to placebo, resulting in an NNH of 34). Cariprazine is associated with no clinically meaningful alterations in metabolic variables, prolactin, or the ECG QT interval. Cariprazine is also approved for the acute treatment of manic or mixed episodes associated with bipolar I disorder. Clinical trials are ongoing in patients with acute bipolar I depression and as adjunctive treatment to antidepressant therapy in patients with major depressive disorder.

Aripiprazole and Haloperidol Activate GSK3β-Dependent Signalling Pathway Differentially in Various Brain Regions of Rats.

Aripiprazole, a dopamine D2 receptor (D2R) partial agonist, possesses a unique clinical profile. Glycogen synthase kinase 3β (GSK3β)-dependent signalling pathways have been implicated in the pathophysiology of schizophrenia and antipsychotic drug actions. The present study examined whether aripiprazole differentially affects the GSK3β-dependent signalling pathways in the prefrontal cortex (PFC), nucleus accumbens (NAc), and caudate putamen (CPu), in comparison with haloperidol (a D2R antagonist) and bifeprunox (a D2R partial agonist). Rats were orally administrated aripiprazole (0.75 mg/kg), bifeprunox (0.8 mg/kg), haloperidol (0.1 mg/kg) or vehicle three times per day for one week. The levels of protein kinase B (Akt), p-Akt, GSK3β, p-GSK3β, dishevelled (Dvl)-3, and β-catenin were measured by Western Blots. Aripiprazole increased GSK3β phosphorylation in the PFC and NAc, respectively, while haloperidol elevated it in the NAc only. However, Akt activity was not changed by any of these drugs. Additionally, both aripiprazole and haloperidol, but not bifeprunox, increased the expression of Dvl-3 and β-catenin in the NAc. The present study suggests that activation of GSK3β phosphorylation in the PFC and NAc may be involved in the clinical profile of aripiprazole; additionally, aripiprazole can increase GSK3β phosphorylation via the Dvl-GSK3β-β-catenin signalling pathway in the NAc, probably due to its relatively low intrinsic activity at D2Rs.

The effect of cariprazine on hostility associated with schizophrenia: post hoc analyses from 3 randomized controlled trials.

Although most patients with schizophrenia are not aggressive, individuals with the disorder have increased risk of hostile behavior. Cariprazine, a dopamine D3 and D2 receptor partial agonist antipsychotic with preferential binding to D3 receptors, was evaluated for antihostility effects in patients with schizophrenia. Post hoc analyses were conducted using pooled data from 3 positive randomized, placebo-controlled, phase 2/3 studies in inpatients (18-60 years) with acute exacerbation of schizophrenia according to DSM-IV-TR criteria; data were collected between 2008 and 2011. The principal post hoc outcome was mean change from baseline to week 6 on the Positive and Negative Syndrome Scale (PANSS) hostility item (P7); separate analyses adjusted for certain PANSS positive symptoms and sedation covariates. Analyses were based on the pooled intent-to-treat population (N = 1,466) using a mixed-effects model for repeated measures approach; separate analyses were conducted in subgroups categorized by baseline hostility item scores (P7: ≥ 2, ≥ 3, ≥ 4). The least squares mean difference (LSMD) in change from baseline to week 6 was statistically significant on all PANSS hostility item analyses in favor of cariprazine versus placebo: unadjusted (-0.28; P < .0001), adjusted for PANSS positive symptoms (-0.12; P < .05), adjusted for positive symptoms plus sedation (-0.12; P < .05). The magnitude of change for cariprazine increased with greater baseline hostility (LSMD vs placebo for ≥ 2, ≥ 3, ≥ 4 subgroups: -0.32, -0.37, -0.51, respectively; P < .01 all). Significant improvement on the hostility item was seen in cariprazine- versus placebo-treated patients with schizophrenia; the effect of cariprazine increased with greater levels of baseline hostility. ClinicalTrials.gov identifiers: NCT00694707, NCT01104766, and NCT01104779.

Efficacy of Low-Dose Aripiprazole to Treat Clozapine-Associated Tardive Dystonia in a Patient with Schizophrenia

Tardive dystonia (TDt) is a debilitating side effect of long-term antipsychotic treatment. Even though TDt is associated with increased psychiatric morbidity, mortality, and severely decreased quality of life, there are no treatment modalities for TDt. Clozapine has been used as a treatment option for TDt in patients with schizophrenia. Interestingly, several recent case reports have indicated that it can enhance or induce TDt. We report a case of clozapine-associated TDt that was treated with low-dose aripiprazole (0.5 mg/day). The patient was a 51-year-old Korean woman with schizophrenia that had been admitted to the psychiatric ward for her florid psychotic symptoms. The patient's TDt symptoms began to develop after 1 year of clozapine (200 mg/day) treatment. Her motor symptoms improved markedly after adding low-dose aripiprazole (0.5 mg/day) to clozapine (175 mg/day). Aripiprazole is a dopamine D2 receptor partial agonist that exhibits partial agonistic activity against serotonin-1A (5-HT1A) receptors and full antagonistic activity against 5-HT2A receptors. The dopaminergic tone in the surrounding milieu is important for aripiprazole activity. In addition, antioxidative effects of aripiprazole may manage the neurotoxic effects of clozapine. To our knowledge, only one report has described a patient with clozapine-associated TDt that was treated with moderate doses of aripiprazole (10-15 mg). This case report may be the first report of low-dose aripiprazole treatment of clozapine-associated TDt.

Cariprazine: First Global Approval.

Cariprazine (Vraylar) is an oral atypical antipsychotic originated by Gedeon Richter. It is a potent dopamine D3 and D2 receptor partial agonist, which preferentially binds to the D3 receptor. Cariprazine also has partial agonist activity at serotonin 5-HT1A receptors. In September 2015, cariprazine received its first global approval in the USA for the treatment of schizophrenia and for the acute treatment of manic or mixed episodes associated with bipolar I disorder. It is also in development in a variety of countries for the treatment of schizophrenia with predominant negative symptoms (phase III), as adjunctive therapy for major depressive disorder (phase II/III) and for the treatment of bipolar depression (phase II). This article summarizes the milestones in the development of cariprazine leading to this first approval for schizophrenia and manic or mixed episodes associated with bipolar I disorder.

Effects of haloperidol and aripiprazole on the human mesolimbic motivational system: A pharmacological fMRI study

The atypical antipsychotic drug aripiprazole is a partial dopamine (DA) D2 receptor agonist, which differentiates it from most other antipsychotics. This study compares the brain activation characteristic produced by aripiprazole with that of haloperidol, a typical D2 receptor antagonist. Healthy participants received an acute oral dose of haloperidol, aripiprazole or placebo, and then performed an active aversive conditioning task with aversive and neutral events presented as sounds, while blood-oxygen-level-dependent (BOLD) functional magnetic resonance imaging (fMRI) was carried out. The fMRI task, targeting the mesolimbic motivational system that is thought to be disturbed in psychosis, was based on the conditioned avoidance response (CAR) animal model – a widely used test of therapeutic potential of antipsychotic drugs. In line with the CAR animal model, the present results show that subjects given haloperidol were not able to avoid more aversive than neutral task trials, even though the response times were shorter during aversive events. In the aripiprazole and placebo groups more aversive than neutral events were avoided. Accordingly, the task-related BOLD-fMRI response in the mesolimbic motivational system was diminished in the haloperidol group compared to the placebo group, particularly in the ventral striatum, whereas the aripiprazole group showed task-related activations intermediate of the placebo and haloperidol groups. The current results show differential effects on brain function by aripiprazole and haloperidol, probably related to altered DA transmission. This supports the use of pharmacological fMRI to study antipsychotic properties in humans.

Effect of cariprazine across the symptoms of mania in bipolar I disorder: Analyses of pooled data from phase II/III trials

Bipolar I disorder is a chronic disorder characterized by episodic recurrences of mania, depression, and mixed affective states interspersed with periods of full or partial remission; subsyndromal residual symptoms between episodes are common and disabling. Cariprazine, an atypical antipsychotic, is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. Post-hoc analyses of pooled data from 3 positive trials were conducted to evaluate the effect of cariprazine 3–12mg/d on the symptoms of mania in inpatients (18–65 years) with bipolar I disorder and a current manic episode. Analyses were based on the pooled intent-to-treat (ITT) population (placebo=429; cariprazine=608). Mean change from baseline to the end of treatment on individual Young Mania Rating Scale (YMRS) items was analysed using a mixed-effects model for repeated measures (MMRM); categorical symptom severity shifts were analysed using logistic regression. Statistically significant improvement in mean change was seen for cariprazine versus placebo on all 11 YMRS items (p<0.0001); significantly more cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment on 11 YMRS items (p<0.0001) and concurrently on the 4 YMRS core symptoms (irritability, speech, content, and disruptive–aggressive behaviour) (p<0.0001). Significantly more cariprazine- versus placebo-treated patients shifted from a Moderate/Worse or Marked/Worse Symptoms categories to Mild/No Symptoms on all 11 (p<0.0001) and 9 of 11 YMRS items (p<0.05), respectively. Results suggest that cariprazine treatment improved mania across YMRS symptoms; a significant percentage of cariprazine- versus placebo-treated patients had mild/no symptoms at the end of treatment.

Brexpiprazole for schizophrenia and as adjunct for major depressive disorder: a systematic review of the efficacy and safety profile for this newly approved antipsychotic - what is the number needed to treat, number needed to harm and likelihood to be helped or harmed?

To describe the efficacy, tolerability and safety of brexpiprazole for the treatment of schizophrenia and as adjunct for major depressive disorder (MDD). The pivotal registration trials were accessed by querying http://www.ncbi.nlm.nih.gov/pubmed/ and http://www.clinicaltrials.gov, for the search terms 'brexpiprazole' OR 'OPC-34712', and by also querying the EMBASE (Elsevier) commercial database for clinical poster abstracts, and by asking the manufacturer for copies of posters presented at congresses. Product labelling provided additional information. All available clinical reports of studies were identified. Descriptions of the principal results and calculation of number needed to treat (NNT) and number needed to harm (NNH) for relevant dichotomous outcomes were extracted from the available study reports and other sources of information. Brexpiprazole is a new dopamine D2 receptor partial agonist that received approval for the treatment of schizophrenia and for adjunctive use for the treatment of MDD based on a clinical trial development programme that included two pivotal Phase III trials of brexpiprazole monotherapy in acute schizophrenia, and two pivotal Phase III trials of adjunctive brexpiprazole in acute MDD in patients who demonstrated inadequate response to standard antidepressant therapy. In addition, results from a 52-week relapse prevention/maintenance randomised placebo-controlled withdrawal study in patients with schizophrenia are available. In these trials, brexpiprazole was administered once daily and titrated to target doses. The recommended dose for the treatment of schizophrenia is 2-4 mg/day and that for MDD, 2 mg/day. Pooling together all the available data for the recommended target dose of brexpiprazole for acute schizophrenia from the above studies, the percentage of responders is 45.5% vs. 31.0% for placebo, yielding a NNT of 7 (95% CI 5-12). In the relapse prevention/maintenance trial, significantly fewer patients relapsed in the brexpiprazole group compared with placebo (13.5% vs. 38.5%), resulting in a NNT of 4 (95% CI 3-8). When the results for brexpiprazole 1, 2 and 3 mg from the two Phase III MDD trials are pooled together, 23.2% of the patients receiving brexpiprazole were responders, vs. 14.5% for placebo, yielding a NNT of 12 (95% CI 8-26). Brexpiprazole was well tolerated - for schizophrenia, discontinuation rates because of an adverse event (AE) were overall lower for patients receiving brexpiprazole vs. placebo, and for MDD a total of 3% of brexpiprazole-treated patients and 1% of placebo-treated patients discontinued because of AEs, resulting in a NNH of 53 (95% CI 30-235). Although the most commonly encountered AE noted in product labelling was akathisia (5.5% in the acute schizophrenia trials and 8.6% in the MDD trials), differences from placebo were small, generating a non-significant NNH of 112 for patients with schizophrenia and a modest NNH of 15 (95% CI 11-23) for patients with MDD. Short-term weight gain appears modest; however, more outliers with an increase of ≥ 7% of body weight were evident in open-label 52-week safety studies. Effects on glucose and lipids were small. Minimal effects on prolactin were observed, and no clinically relevant effects on the ECG QT interval were evident. Clinical trials of brexpiprazole support its efficacy at the recommended target dose of 2-4 mg/day for the treatment of schizophrenia, and at the recommended target dose of 2 mg/day as adjunct to antidepressant medication for the treatment of MDD. Head-to-head comparisons with other available agents among patients with schizophrenia and MDD in the 'real world' are needed.

Nuclear Translocation of Calcium/Calmodulin-dependent Protein Kinase IIδ3 Promoted by Protein Phosphatase-1 Enhances Brain-derived Neurotrophic Factor Expression in Dopaminergic Neurons

We have reported previously that dopamine D2 receptor stimulation activates calcium/calmodulin-dependent protein kinase II (CaMKII) δ3, a CaMKII nuclear isoform, increasing BDNF gene expression. However, the mechanisms underlying that activity remained unclear. Here we report that CaMKIIδ3 is dephosphorylated at Ser(332) by protein phosphatase 1 (PP1), promoting CaMKIIδ3 nuclear translocation. Neuro-2a cells transfected with CaMKIIδ3 showed cytoplasmic and nuclear staining, but the staining was predominantly nuclear when CaMKIIδ3 was coexpressed with PP1. Indeed, PP1 and CaMKIIδ3 coexpression significantly increased nuclear CaMKII activity and enhanced BDNF expression. In support of this idea, chronic administration of the dopamine D2 receptor partial agonist aripiprazole increased PP1 activity and promoted nuclear CaMKIIδ3 translocation and BDNF expression in the rat brain substantia nigra. Moreover, aripiprazole treatment enhanced neurite extension and inhibited cell death in cultured dopaminergic neurons, effects blocked by PP1γ knockdown. Taken together, nuclear translocation of CaMKIIδ3 following dephosphorylation at Ser(332) by PP1 likely accounts for BDNF expression and subsequent neurite extension and survival of dopaminergic neurons.

Unique Effects of Acute Aripiprazole Treatment on the Dopamine D2 Receptor Downstream cAMP-PKA and Akt-GSK3β Signalling Pathways in Rats.

Aripiprazole is a wide-used antipsychotic drug with therapeutic effects on both positive and negative symptoms of schizophrenia, and reduced side-effects. Although aripiprazole was developed as a dopamine D2 receptor (D2R) partial agonist, all other D2R partial agonists that aimed to mimic aripiprazole failed to exert therapeutic effects in clinic. The present in vivo study aimed to investigate the effects of aripiprazole on the D2R downstream cAMP-PKA and Akt-GSK3β signalling pathways in comparison with a D2R antagonist – haloperidol and a D2R partial agonist – bifeprunox. Rats were injected once with aripiprazole (0.75mg/kg, i.p.), bifeprunox (0.8mg/kg, i.p.), haloperidol (0.1mg/kg, i.p.) or vehicle. Five brain regions – the prefrontal cortex (PFC), nucleus accumbens (NAc), caudate putamen (CPu), ventral tegmental area (VTA) and substantia nigra (SN) were collected. The protein levels of PKA, Akt and GSK3β were measured by Western Blotting; the cAMP levels were examined by ELISA tests. The results showed that aripiprazole presented similar acute effects on PKA expression to haloperidol, but not bifeprunox, in the CPU and VTA. Additionally, aripiprazole was able to increase the phosphorylation of GSK3β in the PFC, NAc, CPu and SN, respectively, which cannot be achieved by bifeprunox and haloperidol. These results suggested that acute treatment of aripiprazole had differential effects on the cAMP-PKA and Akt-GSK3β signalling pathways from haloperidol and bifeprunox in these brain areas. This study further indicated that, by comparison with bifeprunox, the unique pharmacological profile of aripiprazole may be attributed to the relatively lower intrinsic activity at D2R.

Antagonist and partial agonist at the dopamine D2 receptors in drug-naïve and non-drug-naïve schizophrenia: a randomized, controlled trial.

Few data are available on the efficacy and safety of antipsychotics with different dopamine D2 receptor (D2-R)-binding properties in drug-naïve and non-drug-naïve schizophrenia. Thus, we aimed to assess whether antipsychotic medication history influences efficacy and tolerability in schizophrenia, based on a randomized controlled study of antipsychotics with mechanisms involving either full antagonism or partial agonism of D2-R. Patients with schizophrenia were recruited and given perospirone or aripiprazole in a 12-week, flexible-dose, open-label, randomized controlled study. Data were analyzed after dividing the patients into antipsychotic-naïve and antipsychotic-treated group according to antipsychotic medication histories. Efficacy and safety were evaluated using the Positive and Negative Syndrome Scale (PANSS), the Drug-Induced Extrapyramidal Symptoms Scale, and the Barnes Akathisia Rating Scale. In patients receiving perospirone, the antipsychotic-naïve group (n = 22) showed greater symptom improvement than that shown by the antipsychotic-treated group (n = 29), as assessed by efficacy evaluation scales such as the PANSS total, positive, and excited component score (p = .006, p < .001, p = .003, respectively). In patients receiving aripiprazole, however, there was no significant difference in efficacy between the antipsychotic-naïve (n = 18) and antipsychotic-treated (n = 31) groups. No significant intra-group or inter-group difference was noted with respect to any of the tolerability-related parameters assessed. The present study data support the hypothesis that antipsychotic medication history may influence efficacy in patients who receive a D2-R full antagonist but not a D2-R partial agonist.

Dopamine receptor partial agonists and addiction

Many drugs abused by humans acutely facilitate, either directly or indirectly, dopamine neurotransmission in the mesolimbic pathway. As a consequence dopamine receptor agonists and antagonists have been widely investigated as putative pharmacological therapies for addiction. This general strategy, however, has had only limited success due in part to poor treatment adherence and efficacy and the significant adverse effects of dopaminergic medications. In this perspective, we discuss the potential therapeutic use of dopamine receptor partial agonists in addiction, developed initially as antipsychotic agents. Recent research indicates that the dopamine D2 receptor partial agonists, such as aripiprazole, also shows useful ancillary efficacy in several animal models of psychostimulant and opioid addiction. Notably, these findings suggest that unlike full dopamine receptor agonists and antagonists these compounds have low abuse liability and are generally well tolerated. Indeed, partial dopamine agonists attenuate the rewarding properties of opioids without interfering with their analgesic effects. Herein we discuss the utility and potential of dopamine receptor partial agonists as treatments for both stimulant and non-stimulant drug addiction.

Brexpiprazole: a new dopamine D₂receptor partial agonist for the treatment of schizophrenia and major depressive disorder.

Brexpiprazole is a dopamine D₂receptor partial agonist. Compared with aripiprazole, it is more potent at 5-HT1A receptors and displays less intrinsic activity at D₂receptors. Brexpiprazole also has potent antagonistic activity at 5-HT2A as well as alpha-adrenergic receptors. In addition to results from phase II trials, data are available from two pivotal phase III, randomized, placebo-controlled trials of brexpiprazole for the acute treatment of schizophrenia and two pivotal phase III, randomized, placebo-controlled trials of adjunctive brexpiprazole for the acute treatment of major depressive disorder in patients with inadequate response to antidepressant medication treatment. Overall tolerability is promising, with rates of discontinuation due to adverse events lower or slightly higher than that observed for placebo. Although overall akathisia was more commonly observed with brexpiprazole than with placebo, the absolute risk increase attributable to brexpiprazole appears small. Short-term weight gain appears modest; however, outliers with an increase of ≥ 7% of body weight were evident in open-label long-term safety studies.

Pretreatment or Posttreatment with Aripiprazole Attenuates Methamphetamine-induced Stereotyped Behavior in Mice

Aripiprazole is a third-generation atypical antipsychotic and a dopamine D2 receptor partial agonist. In the present study, we investigated whether a single administration of aripiprazole to mice, either as a pretreatment or as a posttreatment, would affect stereotypy induced by methamphetamine (METH). Pretreatment of male ICR mice with aripiprazole (1 or 10 mg/kg, i.p.) attenuated the incidence of METH-induced stereotypical behavior in a dose-dependent manner. Pretreatment of mice with 1 mg/kg aripiprazole produced an increase in the locomotor activity in mice treated with METH compared with mice treated with vehicle plus METH and with 10 mg/kg aripiprazole plus METH. This increase in locomotion is indicative of a rightward shift in the dose–response curve for METH, consistent with a shift in the type of stereotypical behavior observed from biting to sniffing. Aripiprazole posttreatment, after METH-induced stereotypical behavior, was fully expressed and also significantly attenuated overall stereotypy in an aripiprazole dose-dependent manner. These data suggest that the antagonism of METH effects by aripiprazole should be investigated as a potential treatment for acute METH overdose.

Novel 5-HT6 receptor antagonists/D2 receptor partial agonists targeting behavioral and psychological symptoms of dementia.

We describe a novel class of designed multiple ligands (DMLs) combining serotonin 5-HT6 receptor (5-HT6R) antagonism with dopamine D2 receptor (D2R) partial agonism. Prototype hybrid molecules were designed using docking to receptor homology models. Diverse pharmacophore moieties yielded 3 series of hybrids with varying invitro properties at 5-HT6R and D2R, and at M1 receptor and hERG channel antitargets. 4-(piperazin-1-yl)-1H-indole derivatives showed highest antagonist potency at 5-HT6R, with 7-butoxy-3,4-dihydroquinolin-2(1H)-one and 2-propoxybenzamide derivatives having promising D2R partial agonism. 2-(3-(4-(1-(phenylsulfonyl)-1H-indol-4-yl)piperazin-1-yl)propoxy)benzamide (47) exhibited nanomolar affinity at both 5-HT6R and D2R and was evaluated in rat models. It displayed potent antidepressant-like and anxiolytic-like activity in the Porsolt and Vogel tests, respectively, more pronounced than that of a reference selective 5-HT6R antagonist or D2R partial agonist. In addition, 47 also showed antidepressant-like activity (Porsolt's test) and anxiolytic-like activity (open field test) in aged (>18-month old) rats. In operant conditioning tests, 47 enhanced responding for sweet reward in the saccharin self-administration test, consistent with anti-anhedonic properties. Further, 47 facilitated extinction of non-reinforced responding for sweet reward, suggesting potential procognitive activity. Taken together, these studies suggest that DMLs combining 5-HT6R antagonism and D2R partial agonism may successfully target affective disorders in patients from different age groups without a risk of cognitive deficits.

Time-resolved FRET binding assay to investigate hetero-oligomer binding properties: proof of concept with dopamine D1/D3 heterodimer.

G protein-coupled receptors (GPCRs) have been described to form hetero-oligomers. The importance of these complexes in physiology and pathology is considered crucial, and heterodimers represent promising new targets to discover innovative therapeutics. However, there is a lack of binding assays to allow the evaluation of ligand affinity for GPCR hetero-oligomers. Using dopamine receptors and more specifically the D1 and D3 receptors as GPCR models, we developed a new time-resolved FRET (TR-FRET) based assay to determine ligand affinity for the D1/D3 heteromer. Based on the high-resolution structure of the dopamine D3 receptor (D3R), six fluorescent probes derived from a known D3R partial agonist (BP 897) were designed, synthesized and evaluated as high affinity and selective ligands for the D3/D2 receptors, and for other dopamine receptor subtypes. The highest affinity ligand 21 was then employed in the development of the D1/D3 heteromer assay. The TR-FRET was monitored between a fluorescent tag donor carried by the D1 receptor (D1R) and a fluorescent acceptor D3R ligand 21. The newly reported assay, easy to implement on other G protein-coupled receptors, constitutes an attractive strategy to screen for heteromer ligands.

Beneficial effect of low-dose mirtazapine in acute aripiprazole-induced akathisia

Low-dose mirtazapine was found to be efficacious for neuroleptic-induced akathisia. We evaluated whether mirtazapine is also effective for akathisia induced by the partial dopamine D2 receptor agonist aripiprazole. Medical charts were retrospectively analyzed for eight patients who developed akathisia while being treated with aripiprazole. All scored at least 2 (mild akathisia) on the Barnes Akathisia Rating Scale (BARS) and were treated with mirtazapine (15 mg/day) for a mean of 8.5 days. There was a statistically significant reduction in the BARS subjective, distress, and global (P<0.01 to P<0.001), but not objective (P=0.21) subscales. Five (62.5%) patients fulfilled the criteria of response, a decrease of at least two points on the BARS global subscale. Low-dose mirtazapine was well tolerated, and mild sedation, the only side effect (three patients), was transient. A large-scale controlled investigation is warranted to substantiate clinical utility of mirtazapine for akathisia induced by aripiprazole and other second-generation antipsychotics.

The efficacy and tolerability of cariprazine in acute mania associated with bipolar I disorder: a phase II trial.

Cariprazine, an orally active and potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors, is being developed for the treatment of schizophrenia and bipolar mania. This Phase II trial evaluated the efficacy, safety, and tolerability of cariprazine versus placebo in the treatment of acute manic or mixed episodes associated with bipolar I disorder. This was a multinational, randomized, double-blind, placebo-controlled, flexible-dose study of cariprazine 3-12mg/day in patients with acute manic or mixed episodes associated with bipolar I disorder. Following washout, patients received three weeks of double-blind treatment. The primary and secondary efficacy parameters were change from baseline to Week 3 in Young Mania Rating Scale (YMRS) and Clinical Global Impressions-Severity (CGI-S) scores, respectively. Post-hoc analysis evaluated changes on YMRS single items. In each group, 118 patients received double-blind treatment; 61.9% of placebo and 63.6% of cariprazine patients completed the study. The overall mean daily dose of cariprazine was 8.8mg/day. At Week 3, cariprazine significantly reduced YMRS and CGI-S scores versus placebo, with least square mean differences of -6.1 (p<0.001) and -0.6 (p<0.001), respectively. On each YMRS item, change from baseline to Week 3 was significantly greater for cariprazine versus placebo (all, p<0.05). A significantly greater percentage of cariprazine patients than placebo patients met YMRS response (48% versus 25%; p<0.001) and remission (42% versus 23%; p=0.002) criteria at Week 3. Adverse events (AEs) led to discontinuation of 12 (10%) placebo and 17 (14%) cariprazine patients. The most common AEs (> 10% for cariprazine) were extrapyramidal disorder, headache, akathisia, constipation, nausea, and dyspepsia. Changes in metabolic parameters were similar between groups, with the exception of fasting glucose; increases in glucose were significantly greater for cariprazine versus placebo (p<0.05). Based on Barnes Akathisia Rating Scale and Simpson-Angus Scale scores, more cariprazine than placebo patients experienced treatment-emergent akathisia (cariprazine: 22%; placebo: 6%) or extrapyramidal symptoms (parkinsonism) (cariprazine: 16%; placebo: 1%). Cariprazine demonstrated superior efficacy versus placebo and was generally well tolerated in patients experiencing acute manic or mixed episodes associated with bipolar I disorder.

EPA-0870 – Efficacy and safety of cariprazine in patients with acute exacerbation of schizophrenia: results of two phase III trials

Introduction Cariprazine is a potent dopamine D3 and D2 receptor partial agonist with preferential binding to D3 receptors. Objective Summarize data from 2 Phase III, randomized, double-blind (6-week), placebo-controlled trials of fixed-dose cariprazine (3mg/d and 6mg/d, NCT01104766) and flexible-dose cariprazine (3–6mg/d and 6–9mg/d, NCT01104779) in adults with acute exacerbation of schizophrenia. Aims Evaluate the efficacy, safety, and tolerability of cariprazine in schizophrenia. Methods Primary and secondary efficacy parameters were change from baseline to Week 6 in Positive and Negative Syndrome Scale (PANSS) and Clinical Global Impressions-Severity (CGI-S), respectively, and were analyzed using a mixed-effects model for repeated measures. Results Randomized patient populations: 617 (NCT01104766; 153 placebo, 155 cariprazine 3mg/d, 157 cariprazine 6mg/d, 152 aripiprazole) and 446 (NCT01104779; 147 placebo, 151 cariprazine 3–6mg/d, 148 cariprazine 6–9mg/d). Improvement from baseline to Week 6 on PANSS total scores was significantly greater with cariprazine vs placebo: least square mean difference (LSMD) was −6.0 (3mg/d, P=.0044), −6.8 (3–6mg/d, P=.0029), −8.8 (6mg/d, P Conclusion Cariprazine was effective and generally well tolerated in the treatment of schizophrenia.

A Structure–Activity Analysis of Biased Agonism at the Dopamine D2 Receptor

Biased agonism offers an opportunity for the medicinal chemist to discover pathway-selective ligands for GPCRs. A number of studies have suggested that biased agonism at the dopamine D2 receptor (D2R) may be advantageous for the treatment of neuropsychiatric disorders, including schizophrenia. As such, it is of great importance to gain insight into the SAR of biased agonism at this receptor. We have generated SAR based on a novel D2R partial agonist, tert-butyl (trans-4-(2-(3,4-dihydroisoquinolin-2(1H)-yl)ethyl)cyclohexyl)carbamate (4). This ligand shares structural similarity to cariprazine (2), a drug awaiting FDA approval for the treatment of schizophrenia, yet displays a distinct bias toward two different signaling end points. We synthesized a number of derivatives of 4 with subtle structural modifications, including incorporation of cariprazine fragments. By combining pharmacological profiling with analytical methodology to identify and to quantify bias, we have demonstrated that efficacy and biased agonism can be finely tuned by minor structural modifications to the head group containing the tertiary amine, a tail group that extends away from this moiety, and the orientation and length of a spacer region between these two moieties.