piperidines and pridopidine

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Development; Humans; Ligands; Neurodegenerative Diseases; Neuroprotective Agents; Piperidines; Receptors, sigma; Sigma-1 Receptor

Huntington's disease (HD) is a highly common inherited monogenic neurodegenerative disease, and the gene responsible for its development is located in the 4p16.3 chromosome. The product of that gene mutation is an abnormal huntingtin (Htt) protein that disrupts the neural conduction, thus leading to motor and cognitive disorders. The disease progresses to irreversible changes in the central nervous system (CNS). Although only a few drugs are available to symptomatic treatment, 'dopamine stabilizers' (as represented by the pridopidine) may be the new treatment options. The underlying causes of HD are dopaminergic conduction disorders. Initially, the disease is hyperkinetic (chorea) until it eventually reaches the hypokinetic phase. Studies confirmed a correlation between the amount of dopamine in the CNS and the stage of the disease. Pridopidine has the capacity to be a dopamine buffer, which could increase or decrease the dopamine content depending on the disease phase. A research carried out on animal models demonstrated the protective effect of pridopidine on nerve cells thanks to its ability to alter the cortical glutamatergic signaling through the N-methyl-D-aspartate (NMDA) receptors. Studies on dopamine stabilizers also reported that pridopidine has a 100-fold greater affinity for the sigma-1 receptor than for the D2 receptor. Disturbances in the activity of sigma-1 receptors occur in neurodegenerative diseases, including HD. Their interaction with pridopidine results in the neuroprotective effect, which is manifested as an increase in the plasticity of synaptic neurons and prevention of their atrophy within the striatum. To determine the effectiveness of pridopidine in the treatment of HD, large multicenter randomized studies such as HART, MermaiHD, and PRIDE-HD were carried out.

Topics: Animals; Dopamine; Humans; Motor Activity; Neurodegenerative Diseases; Neurons; Neuroprotective Agents; Piperidines

The sigma-1 (σ

Topics: Allosteric Regulation; Clinical Trials as Topic; Humans; Ligands; Nervous System Diseases; Piperidines; Receptors, sigma; Sigma-1 Receptor; Small Molecule Libraries

Chorea is defined as jerk-like movements that move randomly from one body part to another. It is due to a variety of disorders and although current symptomatic therapy is quite effective there are few etiology- or pathogenesis-targeted therapies. The aim of this review is to summarize our own experience and published evidence in the treatment of chorea. Areas covered: After evaluating current guidelines and clinical practices for chorea of all etiologies, PubMed was searched for the most recent clinical trials and reviews using the term 'chorea' cross referenced with specific drug names. Expert commentary: Inhibitors of presynaptic vesicular monoamine transporter type 2 (VMAT2) that cause striatal dopamine depletion, such as tetrabenazine, deutetrabenazine, and valbenazine, are considered the treatment of choice in patients with chorea. Some clinicians also use dopamine receptor blockers (e.g. antipsychotics) and other drugs, including anti-epileptics and anti-glutamatargics. 'Dopamine stabilizers' such as pridopidine and other experimental drugs are currently being investigated in the treatment of chorea. Deep brain stimulation is usually reserved for patients with disabling chorea despite optimal medical therapy.

Topics: Antipsychotic Agents; Chorea; Deep Brain Stimulation; Dopamine Antagonists; Humans; Piperidines; Tetrabenazine; Transcranial Magnetic Stimulation; Valine; Vesicular Monoamine Transport Proteins

Despite advances in understanding the pathophysiology of Huntington's disease (HD), there are currently no effective pharmacological agents available to treat core symptoms or to stop or prevent the progression of this hereditary neurodegenerative disorder. Pridopidine, a novel small molecule compound, has demonstrated potential for both symptomatic treatment and disease modifying effects in HD. While pridopidine failed to achieve its primary efficacy outcomes (Modified motor score) in two trials (MermaiHD and HART) there were consistent effects on secondary outcomes (TMS). In the most recent study (PrideHD) pridiopidine did not differ from placebo on TMS, possibly due to a large enduring placebo effect.This review describes the process, based on in vivo systems response profiling, by which pridopidine was discovered and discusses its pharmacological profile, aiming to provide a model for the system-level effects, and a rationale for the use of pridopidine in patients affected by HD. Considering the effects on brain neurochemistry, gene expression and behaviour in vivo, pridopidine displays a unique effect profile. A hallmark feature in the behavioural pharmacology of pridopidine is its state-dependent inhibition or activation of dopamine-dependent psychomotor functions. Such effects are paralleled by strengthening of synaptic connectivity in cortico-striatal pathways suggesting pridopidine has potential to modify phenotypic expression as well as progression of HD. The preclinical pharmacological profile is discussed with respect to the clinical results for pridopidine, and proposals are made for further investigation, including preclinical and clinical studies addressing disease progression and effects at different stages of HD.

Topics: Animals; Corpus Striatum; Dopamine; Gene Expression; Humans; Huntington Disease; Motor Activity; Piperidines

The aim of this review is to overview the pharmacological features of neuroleptics experienced in the treatment of Huntington's disease (HD) symptoms. Despite a large number of case reports, randomized controlled trials (RCT) and drug comparison studies are lacking. Areas covered: After evaluating current guidelines and clinical unmet needs we searched PubMed for the term 'Huntington's disease' cross referenced with the terms 'Antipsychotic drugs' 'Neuroleptic drugs' and single drug specific names. Expert commentary: In clinical practice antipsychotics represent the first choice in the management of chorea in the presence of psychiatric symptoms, when poor compliance is suspected or when there is an increased risk of adverse events due to tetrabenazine. Antipsychotics are considered valid strategies, with the second generation preferred to reduce extrapyramidal adverse events, however they may cause more metabolic side effects. In the future 'dopamine stabilizers', such as pridopidine, could replace antipsychotics modulating dopamine transmission.

Topics: Antipsychotic Agents; Humans; Huntington Disease; Piperidines; Tetrabenazine

Huntington's disease is a rare dominantly-inherited neurodegenerative disease with motor, cognitive and behavioral manifestations. It results from an expanded unstable trinucleotide repeat in the coding region of the huntingtin gene. Treatment is symptomatic, but a poor evidence baseguides selection of therapeutic agents. Non-choreic derangements in voluntary movement contribute to overall motor disability and are poorly addressed by current therapies. Pridopidine is a novel agent in the dopidine class believed to have 'state dependent' effects at dopamine receptors, thus show promise in the treatment of these disorders of voluntary movement.. This review discusses the pharmacokinetics and pharmacodynamics of pridopidine and reviews clinical trials supporting development of the drug for HD. This information was culled from literature searches for dopidines, pridopidine, and HD experimental therapeutics in PubMed and at http://www.clinicaltrials.org .. There is a compelling need to discover new treatments for motor disability in HD, particularly for non-choreic motor symptoms. While pridopidine failed to achieve its primary efficacy outcomes in 2 large trials, reproducible effects on secondary motor outcomes have fueled an ongoing trial studying higher doses and more focused clinical endpoints. This and phase III trials will define define the utility of pridopidine for HD.

Topics: Animals; Dopamine Agents; Humans; Huntington Disease; Piperidines

The first part of the present review describes the exciting journey of dopamine stabilizers, starting in the early eighties with the development of the partial dopamine agonist (-)-3-PPP of phenylpiperidine structure, via various compounds with aminotetraline structure with preferential autoreceptor antagonist properties, and then back again to phenylpiperidine compounds carrying substituents on the aromatic ring that transformed them from partial dopamine agonists to partial dopamine receptor antagonists, such as OSU6162. OSU6162 was brought to the clinic and has in preliminary trials showed antidyskinetic and antipsychotic efficacy. The second part of this review describes results from a hypoglutamatergia mouse model for cognitive symptoms of schizophrenia, where we have tested traditional neuroleptics, new generation antipsychotics with marked 5-HT2 vs dopamine D2 receptor blockade as well as a dopamine stabilizer belonging to the partial dopamine receptor antagonist category.

Topics: Animals; Antipsychotic Agents; Aripiprazole; Disease Models, Animal; Dopamine; Dopamine Agonists; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Glutamic Acid; Mice; Piperazines; Piperidines; Quinolones; Schizophrenia

Open-HART was an open-label extension of HART, a randomized, double-blind, placebo-controlled study of pridopidine in Huntington disease (HD). Previously, we reported safety and exploratory efficacy data after 36 months of treatment with pridopidine 45 mg twice daily. In the interim, emerging data suggests pridopidine may have neuroprotective effects mediated by sigma-1 receptor agonism.. To report additional safety and exploratory efficacy data for continued open-label use of 45 mg BID pridopidine at 48 and 60 months.. Patients in Open-HART were followed up to or greater than 60 months. Adverse events, concomitant medications, vital signs, laboratory values, and ECG data were monitored. Rates of decline in total functional capacity (TFC) and total motor score (TMS) over 60 months were evaluated in an exploratory analysis and compared between Open-HART and placebo recipients from the 2CARE trial. To account for missing data, sensitivity analyses were performed.. Of the original Open-HART baseline cohort (N = 118), 40 remained in the study at 48 months and 33 at 60 months. Pridopidine remained safe and well tolerated over the 60-month interval. TFC and TMS at 48 and 60 months remained stable, showing less decline at these timepoints compared to historical placebo controls from the 2CARE trial. TFC differences at 48 and 60 months observed remained nominally significant after sensitivity analysis.. The 45 mg BID pridopidine dosage remained safe and tolerable over 60 months. Exploratory analyses show TFC and TMS stability at 48 and 60 months, in contrast to placebo historical controls from the 2CARE trial. Results are consistent with data reported from the recent Phase 2 PRIDE-HD trial showing less functional decline in the pridopidine 45 mg BID treated group at 52 weeks.

Topics: Adult; Aged; Double-Blind Method; Female; Follow-Up Studies; Humans; Huntington Disease; Male; Middle Aged; Neuroprotective Agents; Outcome Assessment, Health Care; Piperidines; Receptors, sigma; Sigma-1 Receptor

No pharmacological treatment has been demonstrated to provide a functional benefit for persons with Huntington's disease (HD). Pridopidine is a sigma-1-receptor agonist shown to have beneficial effects in preclinical models of HD.. To further explore the effect of pridopidine on Total Functional Capacity (TFC) in the recent double-blind, placebo-controlled PRIDE-HD study.. We performed post-hoc analyses to evaluate the effect of pridopidine on TFC at 26 and 52 weeks. Participants were stratified according to baseline TFC score and analyzed using repeated measures (MMRM) and multiple imputation assuming missing not-at-random (MNAR) and worst-case scenarios.. The pridopidine 45 mg bid dosage demonstrated a beneficial effect on TFC for the entire population at week 52 of 0.87 (nominal p = 0.0032). The effect was more pronounced for early HD participants (HD1/HD2, TFC = 7-13), with a change from placebo of 1.16 (nominal p = 0.0003). This effect remained nominally significant using multiple imputation with missing not at random assumption as a sensitivity analysis. Responder analyses showed pridopidine 45 mg bid reduced the probability of TFC decline in early HD patients at Week 52 (nominal p = 0.02).. Pridopidine 45 mg bid results in a nominally significant reduction in TFC decline at 52 weeks compared to placebo, particularly in patients with early-stage HD.

Topics: Activities of Daily Living; Adult; Female; Functional Status; Humans; Huntington Disease; Male; Middle Aged; Piperidines; Receptors, sigma; Severity of Illness Index; Sigma-1 Receptor

Previous trials have shown that pridopidine might reduce motor impairment in patients with Huntington's disease. The aim of this study was to ascertain whether higher doses of pridopidine than previously tested reduce motor symptoms in a dose-dependent manner while maintaining acceptable safety and tolerability.. PRIDE-HD was a randomised, placebo-controlled, phase 2, dose-ranging study in adults (aged ≥21 years) with Huntington's disease at outpatient clinics in 53 sites across 12 countries (Australia, Austria, Canada, Denmark, France, Germany, Italy, Poland, Russia, the Netherlands, the UK, and the USA). Eligible patients had clinical onset after age 18 years, 36 or more cytosine-adenine-guanine repeats in the huntingtin gene, motor symptoms (Unified Huntington's Disease Rating Scale total motor score [UHDRS-TMS] ≥25 points), and reduced independence (UHDRS independence score ≤90%). Patients were randomly assigned (1:1:1:1:1) with centralised interactive-response technology to receive one of four doses of pridopidine (45, 67·5, 90, or 112·5 mg) or placebo orally twice a day for 52 weeks. Randomisation was stratified within centres by neuroleptic drug use. The primary efficacy endpoint was change in the UHDRS-TMS from baseline to 26 weeks, which was assessed in all randomised patients who received at least one dose of study drug and had at least one post-baseline efficacy assessment (full analysis set). Participants and investigators were masked to treatment assignment. This trial is registered with EudraCT (2013-001888-23) and ClinicalTrials.gov (NCT02006472).. Between Feb 13, 2014, and July 5, 2016, 408 patients were enrolled and randomly assigned to receive placebo (n=82) or pridopidine 45 mg (n=81), 67·5 mg (n=82), 90 mg (n=81), or 112·5 mg (n=82) twice daily for 26 weeks. The full analysis set included 397 patients (81 in the placebo group, 75 in the 45 mg group, 79 in the 67·5 mg group, 81 in the 90 mg group, and 81 in the 112·5 mg group). Pridopidine did not significantly change the UHDRS-TMS at 26 weeks compared with placebo at any dose. The most frequent adverse events across all groups were diarrhoea, vomiting, nasopharyngitis, falls, headache, insomnia, and anxiety. The most common treatment-related adverse events were insomnia, diarrhoea, nausea, and dizziness. Serious adverse events occurred in the pridopidine groups only and were most frequently falls (n=5), suicide attempt (n=4), suicidal ideation (n=3), head injury (n=3), and aspiration pneumonia (n=3). No new safety or tolerability concerns emerged in this study. One death in the pridopidine 112·5 mg group due to aspiration pneumonia was considered to be possibly related to the study drug.. Pridopidine did not improve the UHDRS-TMS at week 26 compared with placebo and, thus, the results of secondary or tertiary analyses in previous trials were not replicated. A potentially strong placebo effect needs to be ruled out in future studies.. Teva Pharmaceutical Industries.

Topics: Adult; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Huntington Disease; Male; Middle Aged; Piperidines; Severity of Illness Index; Treatment Outcome

Open-HART is an open-label extension of HART, a randomized, placebo-controlled, dose-ranging, parallel-group study.. To evaluate safety and exploratory efficacy of open-label pridopidine over 36 months in subjects with Huntington's disease (HD).. Open-HART subjects were treated with pridopidine 45 mg twice daily (BID). After initial evaluation by telephone (Week 1) and in person (Month 1), in-person visits occurred every 3 months, alternating between safety and clinical visits (safety plus Unified Huntington's Disease Rating Scale [UHDRS] assessment). The UHDRS was performed for pre-specified analysis as a secondary outcome measure. Adverse events (AEs), laboratory values, and electrocardiography were monitored throughout.. Most subjects (89%) reported at least one AE, with 30% experiencing treatment-related AEs. The most common AEs during the first year were falls (12.7%), anxiety (9.3%), insomnia (8.5%), irritability (6.8%), and depression (5.9%). Ninety-nine percent of subjects took concomitant medications. Two seizures were reported as AEs. No arrhythmias or suicide attempts were reported. Five deaths occurred, all considered treatment unrelated. Secondary exploratory analyses of subjects on pridopidine demonstrated motor deterioration (as measured by the UHDRS total motor score) consistent with HD's natural history, as shown in large observational studies. A post-hoc, exploratory analysis of TFC performance compared to placebo groups from other long-term HD studies demonstrated no significant effect for pridopidine on TFC progression after correction for multiple comparisons.. Pridopidine 45 mg BID was generally safe and tolerable in HD subjects over 36 months. TMS declined in a manner consistent with the known natural history of HD.

Topics: Adult; Canada; Cohort Studies; Dopamine Agents; Dose-Response Relationship, Drug; Female; Humans; Huntington Disease; Male; Middle Aged; Piperidines; Severity of Illness Index; Time Factors; Treatment Outcome; United States

Pridopidine, a new oral drug for treatment of patients with motor symptoms associated with Huntington's Disease (HD) is currently under development. In steady-state conditions, pridopidine elimination is mediated primarily through renal excretion. This study evaluated single dose and steady-state pharmacokinetics (PK) of a daily dose of pridopidine in subjects with mild and moderate renal impairment and matched healthy subjects.. Subjects with mild renal impairment (n = 12), moderate impairment (n = 12), or their matched healthy controls (n = 25) participated in this study. Subjects received a single dose of pridopidine (45 mg) on day 1 and a multiple dose cycle of 45 mg once daily on days 5-18. Blood and urine samples were collected on days 1 and 18 for PK analysis.. Mild renal impairment did not affect the PK of pridopidine whilst an increase in exposure was seen in subjects with moderate renal impairment. Subjects with moderate impairment showed reduced plasma clearance (by 44%) and had 68% higher AUC (90% CI 1.22, 2.30) and 26% higher Cmax (90% CI 1.02, 1.56) values than those with normal renal function at steady-state. Pridopidine was safe and well tolerated in healthy subjects and in subjects with mild and moderate renal impairment.. Mild renal impairment has no impact on exposure to pridopidine while moderately impaired renal function resulted in higher pridopidine concentrations.

Topics: Adolescent; Adult; Aged; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Female; Germany; Humans; Huntington Disease; Kidney Diseases; Kidney Function Tests; Male; Middle Aged; Piperidines; Severity of Illness Index; Young Adult

To assess the 1-year safety profile of the dopaminergic stabilizer pridopidine in patients with Huntington disease.. Patients received pridopidine 45 mg/day for 4 weeks then pridopidine 90 mg/day for 22 weeks in this 6-month open-label extension (OLE) of the 6-month MermaiHD randomized controlled trial (RCT). Any adverse events (AEs) were recorded. Patients were categorized by their RCT treatment group (placebo, pridopidine 45 mg/day, pridopidine 90 mg/day).. Of the 386 patients who completed the RCT, 353 entered the OLE and 305 (86.4%) completed. In 1 year, similar percentages of patients from each group reported ≥1 AE (placebo, 79.6% [n = 90/113]; 45 mg/day, 80.8% [n = 101/125]; 90 mg/day, 82.6% [n = 95/115]) and ≥1 serious AE (8.0% [n = 9/113], 12.8% [n = 16/125], and 8.7% [n = 10/115], respectively). The AE profile across both studies was similar; falls and worsening of chorea were most commonly reported. During the OLE, more patients previously receiving pridopidine reported ≥1 AE (67.9% [n = 163/240]) than those who had received placebo (56.6% [n = 64/113]). Early in the RCT, small increases in heart rate were reported in patients receiving pridopidine. During 1 year, no clinically meaningful changes in laboratory parameters or EKG-related safety concerns were identified.. Pridopidine (≤90 mg/day) has an acceptable safety profile and is well-tolerated for 1 year.. This study provides Class IV evidence that pridopidine (≤90 mg/day) is generally safe and well-tolerated in patients with Huntington disease for up to 1 year.

Topics: Adult; Depression; Dizziness; Female; Humans; Huntington Disease; Male; Middle Aged; Piperidines; Time Factors; Treatment Outcome

We examined the effects of 3 dosages of pridopidine, a dopamine-stabilizing compound, on motor function and other features of Huntington's disease, with additional evaluation of its safety and tolerability. This was a randomized, double-blind, placebo-controlled trial in outpatient neurology clinics at 27 sites in the United States and Canada. Two hundred twenty-seven subjects enrolled from October 24, 2009, to May 10, 2010. The intervention was pridopidine, either 20 (n=56), 45 (n=55), or 90 (n=58) mg daily for 12 weeks or matching placebo (n=58). The primary outcome measure was the change from baseline to week 12 in the Modified Motor Score, a subset of the Unified Huntington's Disease Rating Scale Total Motor Score. Measures of safety and tolerability included adverse events and trial completion on the assigned dosage. After 12 weeks, the treatment effect (relative to placebo, where negative values indicate improvement) of pridopidine 90 mg/day on the Modified Motor Score was -1.2 points (95% confidence interval [CI], -2.5 to 0.1 points; P = .08). The effect on the Total Motor Score was -2.8 points (95% CI, -5.4 to -0.1 points; nominal P = .04). No significant effects were seen in secondary outcome measures with any of the active dosages. Pridopidine was generally well tolerated. Although the primary analysis did not demonstrate a statistically significant treatment effect, the overall results suggest that pridopidine may improve motor function in Huntington's disease. The 90 mg/day dosage appears worthy of further study. Pridopidine was well tolerated.

Topics: Adult; Behavior; Cognition; Data Interpretation, Statistical; Dopamine Agents; Dose-Response Relationship, Drug; Double-Blind Method; Female; Humans; Huntington Disease; Male; Movement; Piperidines; Trail Making Test; Treatment Outcome

Pridopidine is being developed for the treatment of impaired motor function associated with Huntington's disease and belongs to a new class of compounds known as dopidines, which act as dopaminergic stabilizers. In vitro studies have shown that pridopidine is a substrate for the P450 cytochrome 2D6 enzyme (CYP2D6), and clinical data show that the half-life of pridopidine is different following single dosing versus at steady state. To further investigate the pharmacokinetic profile of pridopidine and to establish whether dose adjustment is needed in poor CYP2D6 metabolizers, a single-centre, open-label, multiple-dose study in healthy volunteers was performed. In total, 24 extensive CYP2D6 metabolizers (EMs) and 12 poor CYP2D6 metabolizers (PMs) were enrolled. Both groups received 45 mg pridopidine twice daily (b.i.d.). Plasma samples were taken during the first day of b.i.d. dosing (Day 1) and at steady state, following 14 days of b.i.d. dosing. At Day 1, total exposure in PMs was almost three times higher than those in EMs (AUC0-∞ = 11,192 and 3,782 h·ng/mL, respectively; PM/EM ratio = 2.96; p < 0.001). However, at steady state, PMs and EMs had comparable exposure due to a reduction in pridopidine elimination in EMs over time. Thus, at steady-state peak (C max) and total (AUC0-24) exposures were only 1.24 and 1.29 times higher, respectively, in PMs than EMs. These results support that pridopidine is a CYP2D6 auto-inhibitor. Pridopidine was well tolerated in both EMs and PMs. The slightly higher exposure level in PMs at steady state does not indicate a need for dose adjustment or genotyping for CYP2D6 metabolizer status.

Topics: Administration, Oral; Adult; Analysis of Variance; Area Under Curve; Cytochrome P-450 CYP2D6; Denmark; Dopamine Agents; Drug Administration Schedule; Female; Genotype; Half-Life; Humans; Male; Metabolic Clearance Rate; Middle Aged; Models, Biological; Pharmacogenetics; Phenotype; Piperidines

The influence of the cytochrome P450 enzyme CYP2D6 in the metabolism of the novel dopaminergic stabilizer pridopidine was investigated in healthy Swedish Caucasians.. Six extensive metabolizers (EM) and six poor metabolizers (PM) of debrisoquine were given a single oral dose of pridopidine (EM, 50 mg; PM, 25 mg).. The mean total plasma clearance of pridopidine was 541 and 138 mL/min in EM and PM, respectively (p = 0.003), and was slightly higher in PM than the mean renal plasma clearance (105 mL/min; p = 0.11). The mean plasma area under the time-concentration curve between time zero and 32 h (AUC(0-32 h)) of the N-depropyl metabolite ACR30 was higher in EM than in PM (1,377 vs. 61 nmol h/mL, respectively; p < 0.001). The urinary excretion of pridopidine + ACR30 was high in both EM (85 %) and PM (78 %). The dose-adjusted peak concentration (C(max)) was not statistically different in EM and PM; consequently, the oral absorption of pridopidine was close to complete.. Following a single dose of pridopidine, the drug is N-depropylated by CYP2D6 in EM, while in PM the most important elimination pathway is renal glomerular filtration. Results of studies examining the effects of multiple repeat dosing suggest that the CYP2D6 enzyme is at least partly inactivated by pridopidine.

Topics: Administration, Oral; Adult; Area Under Curve; Biotransformation; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Dealkylation; Dopamine Antagonists; Enzyme Inhibitors; Glomerular Filtration Rate; Half-Life; Humans; Intestinal Absorption; Kidney; Metabolic Clearance Rate; Middle Aged; Phenotype; Piperidines; Sweden; White People; Young Adult

Huntington's disease is a progressive neurodegenerative disorder, characterised by motor, cognitive, and behavioural deficits. Pridopidine belongs to a new class of compounds known as dopaminergic stabilisers, and results from a small phase 2 study in patients with Huntington's disease suggested that this drug might improve voluntary motor function. We aimed to assess further the effects of pridopidine in patients with Huntington's disease.. We undertook a 6 month, randomised, double-blind, placebo-controlled trial to assess the efficacy of pridopidine in the treatment of motor deficits in patients with Huntington's disease. Our primary endpoint was change in the modified motor score (mMS; derived from the unified Huntington's disease rating scale) at 26 weeks. We recruited patients with Huntington's disease from 32 European centres; patients were aged 30 years or older and had an mMS of 10 points or greater at baseline. Patients were randomly assigned (1:1:1) to receive placebo, 45 mg per day pridopidine, or 90 mg per day pridopidine by use of centralised computer-generated codes. Patients and investigators were masked to treatment assignment. We also assessed the safety and tolerability profile of pridopidine. For our primary analysis, all patients were eligible for inclusion in our full analysis set, in which we used the last observation carried forward method for missing values. We used an analysis of covariance model and the Bonferroni method to adjust for multiple comparisons. We used a prespecified per-protocol population as our sensitivity analysis. The α level was 0·025 for our primary analysis and 0·05 overall. This trial is registered with ClinicalTrials.gov, number NCT00665223.. At 26 weeks, in our full analysis set the difference in mean mMS was -0·99 points (97·5% CI -2·08 to 0·10, p=0·042) in patients who received 90 mg per day pridopidine (n=145) versus those who received placebo (n=144), and -0·36 points (-1·44 to 0·72, p=0·456) in those who received 45 mg per day pridopidine (n=148) versus those who received placebo. At the 90 mg per day dose, in our per-protocol population (n=114), the reduction in the mMS was of -1·29 points (-2·47 to -0·12; p=0·014) compared with placebo (n=120). We did not identify any changes in non-motor endpoints at either dose. Pridopidine was well tolerated and had an adverse event profile similar to that of placebo.. This study did not provide evidence of efficacy as measured by the mMS, but a potential effect of pridopidine on the motor phenotype of Huntington's disease merits further investigation. Pridopidine up to 90 mg per day was well tolerated in patients with Huntington's disease.. NeuroSearch A/S.

Topics: Adult; Aged; Double-Blind Method; Female; Humans; Huntington Disease; Male; Middle Aged; Motor Activity; Piperidines; Treatment Outcome

Amyotrophic lateral sclerosis (ALS) is a lethal and incurable neurodegenerative disease due to the loss of upper and lower motor neurons, which leads to muscle weakness, atrophy, and paralysis. Sigma-1 receptor (σ-1R) is a ligand-operated protein that exhibits pro-survival and anti-apoptotic properties. In addition, mutations in its codifying gene are linked to development of juvenile ALS pointing to an important role in ALS. Here, we investigated the disease-modifying effects of pridopidine, a σ-1R agonist, using a delayed onset SOD1 G93A mouse model of ALS. Mice were administered a continuous release of pridopidine (3.0 mg/kg/day) for 4 weeks starting before the appearance of any sign of muscle weakness. Mice were monitored weekly and several behavioural tests were used to evaluate muscle strength, motor coordination and gait patterns. Pridopidine-treated SOD1 G93A mice showed genotype-specific effects with the prevention of cachexia. In addition, these effects exhibited significant improvement of motor behaviour 5 weeks after treatment ended. However, the survival of the animals was not extended. In summary, these results show that pridopidine can modify the disease phenotype of ALS-associated cachexia and motor deficits in a SOD1 G93A mouse model.

Topics: Amyotrophic Lateral Sclerosis; Animals; Cachexia; Disease Models, Animal; Mice; Mice, Transgenic; Muscle Weakness; Neurodegenerative Diseases; Phenotype; Piperidines; Superoxide Dismutase; Superoxide Dismutase-1

Huntington disease (HD) is a neurodegenerative disorder caused by polyglutamine-encoding CAG repeat expansion in the huntingtin (HTT) gene. HTT is involved in the axonal transport of vesicles containing brain-derived neurotrophic factor (BDNF). In HD, diminished BDNF transport leads to reduced BDNF delivery to the striatum, contributing to striatal and cortical neuronal death. Pridopidine is a selective and potent sigma-1 receptor (S1R) agonist currently in clinical development for HD. The S1R is located at the endoplasmic reticulum (ER)-mitochondria interface, where it regulates key cellular pathways commonly impaired in neurodegenerative diseases. We used a microfluidic device that reconstitutes the corticostriatal network, allowing the investigation of presynaptic dynamics, synaptic morphology and transmission, and postsynaptic signaling. Culturing primary neurons from the HD mouse model Hdh

Topics: Animals; Brain; Brain-Derived Neurotrophic Factor; Disease Models, Animal; Glutamates; Homeostasis; Huntingtin Protein; Huntington Disease; Lab-On-A-Chip Devices; Mice; Neuroprotective Agents; Piperidines; Synapses

Optic neuropathies such as glaucoma are characterized by retinal ganglion cell (RGC) degeneration and death. The sigma-1 receptor (S1R) is an attractive target for treating optic neuropathies as it is highly expressed in RGCs, and its absence causes retinal degeneration. Activation of the S1R exerts neuroprotective effects in models of retinal degeneration. Pridopidine is a highly selective and potent S1R agonist in clinical development. We show that pridopidine exerts neuroprotection of retinal ganglion cells in two different rat models of glaucoma. Pridopidine strongly binds melanin, which is highly expressed in the retina. This feature of pridopidine has implications to its ocular distribution, bioavailability, and effective dose. Mitochondria dysfunction is a key contributor to retinal ganglion cell degeneration. Pridopidine rescues mitochondrial function via activation of the S1R, providing support for the potential mechanism driving its neuroprotective effect in retinal ganglion cells.

Topics: Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Glaucoma; Mitochondria; Neuroprotective Agents; Piperidines; Rats; Reactive Oxygen Species; Receptors, sigma; Retinal Ganglion Cells; Sigma-1 Receptor

Using [. S1R occupancy as function of pridopidine dose (or plasma concentration) in HVs could be described by a three-parameter Hill equation with a Hill coefficient larger than one. A high degree of S1R occupancy (87% to 91%) was found throughout the brain at pridopidine doses ranging from 22.5 to 90 mg. S1R occupancy was 43% at 1 mg pridopidine. In contrast, at 90 mg pridopidine, the D2/D3R occupancy was only minimal (~ 3%).. Our PET findings indicate that at clinically relevant single dose of 90 mg, pridopidine acts as a selective S1R ligand showing near to complete S1R occupancy with negligible occupancy of the D2/D3R. The dose S1R occupancy relationship suggests cooperative binding of pridopidine to the S1R. Our findings provide significant clarification about pridopidine's mechanism of action and support further use of the 45-mg twice-daily dose to achieve full and selective targeting of the S1R in future clinical trials of neurodegenerative disorders. Clinical Trials.gov Identifier: NCT03019289 January 12, 2017; EUDRA-CT-Nr. 2016-001757-41.

Topics: Benzamides; Benzofurans; Brain; Dopamine; Healthy Volunteers; Humans; Huntington Disease; Male; Piperidines; Positron-Emission Tomography; Receptors, Dopamine D2; Receptors, Dopamine D3

Topics: Animals; Coculture Techniques; Disease Models, Animal; Female; Humans; Huntington Disease; Hydrogen Peroxide; Male; Mice; Mice, Transgenic; Mitochondria; Neural Stem Cells; Piperidines; Pregnancy; Receptors, sigma; Sigma-1 Receptor

The endoplasmic reticulum (ER)-localized Sigma-1 receptor (S1R) is neuroprotective in models of neurodegenerative diseases, among them Huntington disease (HD). Recent clinical trials in HD patients and preclinical studies in cellular and mouse HD models suggest a therapeutic potential for the high-affinity S1R agonist pridopidine. However, the molecular mechanisms of the cytoprotective effect are unclear. We have previously reported strong induction of ER stress by toxic mutant huntingtin (mHtt) oligomers, which is reduced upon sequestration of these mHtt oligomers into large aggregates. Here, we show that pridopidine significantly ameliorates mHtt-induced ER stress in cellular HD models, starting at low nanomolar concentrations. Pridopidine reduced the levels of markers of the three branches of the unfolded protein response (UPR), showing the strongest effects on the PKR-like endoplasmic reticulum kinase (PERK) branch. The effect is S1R-dependent, as it is abolished in cells expressing mHtt in which the S1R was deleted using CRISPR/Cas9 technology. mHtt increased the level of the detergent-insoluble fraction of S1R, suggesting a compensatory cellular mechanism that responds to increased ER stress. Pridopidine further enhanced the levels of insoluble S1R, suggesting the stabilization of activated S1R oligomers. These S1R oligomeric species appeared in ER-localized patches, and not in the mitochondria-associated membranes nor the ER-derived quality control compartment. The colocalization of S1R with the chaperone BiP was significantly reduced by mHtt, and pridopidine restored this colocalization to normal, unstressed levels. Pridopidine increased toxic oligomeric mHtt recruitment into less toxic large sodium dodecyl sulfate-insoluble aggregates, suggesting that this in turn reduces ER stress and cytotoxicity.

Topics: 3T3 Cells; Animals; CRISPR-Cas Systems; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress; Gene Knockout Techniques; Heat-Shock Proteins; HEK293 Cells; Humans; Huntingtin Protein; Mice; Mitochondrial Membranes; Piperidines; Receptors, sigma; Sigma-1 Receptor; Unfolded Protein Response

Topics: Humans; Huntington Disease; Piperidines

Topics: Alzheimer Disease; Animals; Dendritic Spines; Disease Models, Animal; Excitatory Postsynaptic Potentials; Hippocampus; Mice; Mice, Inbred C57BL; Neuroprotective Agents; Piperidines; Receptors, sigma; Sigma-1 Receptor; Synapses

Pridopidine is a small molecule in clinical development for the treatment of Huntington's disease. It was recently found to have high binding affinity to the sigma-1 receptor, a chaperone protein involved in cellular defense mechanisms and neuroplasticity. Here, we have evaluated the neuroprotective and neurorestorative effects of pridopidine in a unilateral 6-hydroxydopamine (6-OHDA) lesion model of parkinsonism in mice. By 5 weeks of daily administration, a low dose of pridopidine (0.3 mg/kg) had significantly improved deficits in forelimb use (cylinder test, stepping test) and abolished the ipsilateral rotational bias typical of hemiparkinsonian animals. A higher dose of pridopidine (1 mg/kg) significantly improved only the rotational bias, with a trend towards improvement in forelimb use. The behavioral recovery induced by pridopidine 0.3 mg/kg was accompanied by a significant protection of nigral dopamine cell bodies, an increased dopaminergic fiber density in the striatum, and striatal upregulation of GDNF, BDNF, and phosphorylated ERK1/2. The beneficial effects of pridopidine 0.3 mg/kg were absent in 6-OHDA-lesioned mice lacking the sigma-1 receptor. Pharmacokinetic data confirmed that the effective dose of pridopidine reached brain concentrations sufficient to bind S1R. Our results are the first to show that pridopidine promotes functional neurorestoration in the damaged nigrostriatal system acting via the sigma-1 receptor.

Topics: Animals; Dopaminergic Neurons; Female; Male; Mice; Motor Skills; Neuroprotective Agents; Oxidopamine; Parkinson Disease, Secondary; Piperidines; Receptors, sigma; Sigma-1 Receptor; Substantia Nigra

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease affecting both the upper and lower motor neurons (MNs), with no effective treatment currently available. Early pathological events in ALS include perturbations in axonal transport (AT), formation of toxic protein aggregates and Neuromuscular Junction (NMJ) disruption, which all lead to axonal degeneration and motor neuron death. Pridopidine is a small molecule that has been clinically developed for Huntington disease. Here we tested the efficacy of pridopidine for ALS using in vitro and in vivo models. Pridopidine beneficially modulates AT deficits and diminishes NMJ disruption, as well as motor neuron death in SOD1

Topics: Amyotrophic Lateral Sclerosis; Animals; Axonal Transport; Cell Death; Cell Survival; Cells, Cultured; Coculture Techniques; Disease Models, Animal; Female; MAP Kinase Signaling System; Mice; Mice, Inbred C57BL; Mice, Inbred ICR; Mice, Transgenic; Motor Neurons; Muscle Cells; Myoblasts, Smooth Muscle; Neuromuscular Junction; Piperidines; Receptors, sigma; Sigma-1 Receptor; Spinal Cord; Superoxide Dismutase-1

Familial Dysautonomia (FD) is an autosomal recessive congenital neuropathy that results from a point mutation at the 5' splice site of intron 20 in the IKBKAP gene. This mutation decreases production of the IKAP protein, and treatments that increase the level of the full-length IKBKAP transcript are likely to be of therapeutic value. We previously found that phosphatidylserine (PS), an FDA-approved food supplement, elevates IKAP levels in cells generated from FD patients. Here we demonstrate that combined treatment of cells generated from FD patients with PS and kinetin or PS and the histone deacetylase inhibitor trichostatin A (TSA) resulted in an additive elevation of IKAP compared to each drug alone. This indicates that the compounds influence different pathways. We also found that pridopidine enhances production of IKAP in cells generated from FD patients. Pridopidine has an additive effect on IKAP levels when used in combination with kinetin or TSA, but not with PS; suggesting that PS and pridopidine influence IKBKAP levels through the same mechanism. Indeed, we demonstrate that the effect of PS and pridopidine is through sigma-1 receptor-mediated activation of the BDNF signaling pathway. A combination treatment with any of these drugs with different mechanisms has potential to benefit FD patients.

Topics: Brain-Derived Neurotrophic Factor; Carrier Proteins; Cells, Cultured; Dose-Response Relationship, Drug; Drug Therapy, Combination; Dysautonomia, Familial; Fibroblasts; Gene Expression; Histone Deacetylase Inhibitors; Humans; Kinetin; MAP Kinase Signaling System; Phosphatidylserines; Piperidines; Transcriptional Elongation Factors; Treatment Outcome; Tubulin

Huntington's disease (HD) is a neurodegenerative disease caused by a CAG repeat expansion in the Huntingtin gene (HTT), translated into a Huntingtin protein with a polyglutamine expansion. There is preferential loss of medium spiny neurons within the striatum and cortical pyramidal neurons. Pridopidine is a small molecule showing therapeutic potential in HD preclinical and clinical studies. Pridopidine has nanomolar affinity to the sigma-1 receptor (sigma-1R), which is located predominantly at the endoplasmic reticulum (ER) and mitochondrial associated ER membrane, and activates neuroprotective pathways. Here we evaluate the neuroprotective effects of pridopidine against mutant Huntingtin toxicity in mouse and human derived in vitro cell models. We also investigate the involvement of the sigma-1 receptor in the mechanism of pridopidine. Pridopidine protects mutant Huntingtin transfected mouse primary striatal and cortical neurons, with an EC50 in the mid nanomolar range, as well as HD patient-derived induced pluripotent stem cells (iPSCs). This protection by pridopidine is blocked by NE-100, a purported sigma-1 receptor antagonist, and not blocked by ANA-12, a reported TrkB receptor antagonist. 3PPP, a documented sigma-1 receptor agonist, shows similar neuroprotective effects. Genetic knock out of the sigma-1 receptor dramatically decreases protection from pridopidine and 3PPP, but not protection via brain derived neurotrophic factor (BDNF). The neuroprotection afforded by pridopidine in our HD cell models is robust and sigma-1 receptor dependent. These studies support the further development of pridopidine, and other sigma-1 receptor agonists as neuroprotective agents for HD and perhaps for other disorders.

Topics: Animals; Cells, Cultured; Humans; Huntingtin Protein; Huntington Disease; Mice; Mice, Knockout; Neurons; Neuroprotective Agents; Piperidines; Receptors, sigma; Sigma-1 Receptor

Huntington Disease (HD) is an incurable autosomal dominant neurodegenerative disorder driven by an expansion repeat giving rise to the mutant huntingtin protein (mHtt), which is known to disrupt a multitude of transcriptional pathways. Pridopidine, a small molecule in development for treatment of HD, has been shown to improve motor symptoms in HD patients. In HD animal models, pridopidine exerts neuroprotective effects and improves behavioral and motor functions. Pridopidine binds primarily to the sigma-1 receptor, (IC50 ~ 100 nM), which mediates its neuroprotective properties, such as rescue of spine density and aberrant calcium signaling in HD neuronal cultures. Pridopidine enhances brain-derived neurotrophic factor (BDNF) secretion, which is blocked by putative sigma-1 receptor antagonist NE-100, and was shown to upregulate transcription of genes in the BDNF, glucocorticoid receptor (GR), and dopamine D1 receptor (D1R) pathways in the rat striatum. The impact of different doses of pridopidine on gene expression and transcript splicing in HD across relevant brain regions was explored, utilizing the YAC128 HD mouse model, which carries the entire human mHtt gene containing 128 CAG repeats.. RNAseq was analyzed from striatum, cortex, and hippocampus of wild-type and YAC128 mice treated with vehicle, 10 mg/kg or 30 mg/kg pridopidine from the presymptomatic stage (1.5 months of age) until 11.5 months of age in which mice exhibit progressive disease phenotypes.. The most pronounced transcriptional effect of pridopidine at both doses was observed in the striatum with minimal effects in other regions. In addition, for the first time pridopidine was found to have a dose-dependent impact on alternative exon and junction usage, a regulatory mechanism known to be impaired in HD. In the striatum of YAC128 HD mice, pridopidine treatment initiation prior to symptomatic manifestation rescues the impaired expression of the BDNF, GR, D1R and cAMP pathways.. Pridopidine has broad effects on restoring transcriptomic disturbances in the striatum, particularly involving synaptic transmission and activating neuroprotective pathways that are disturbed in HD. Benefits of treatment initiation at early disease stages track with trends observed in the clinic.

Topics: Animals; Brain; Gene Expression; Gene Expression Profiling; Humans; Huntington Disease; Mice; Mice, Transgenic; Neuroprotection; Neuroprotective Agents; Piperidines; Synaptic Transmission

Topics: Biomarkers; Clinical Trials as Topic; Disease Progression; Endpoint Determination; Humans; Huntington Disease; Molecular Targeted Therapy; Oligonucleotides, Antisense; Piperidines; Placebo Effect

Pridopidine, a compound in clinical trials for Huntington's disease treatment, was originally synthesized as a dopamine D2 receptor (D2R) ligand, but later found to possess higher affinity for the sigma-1 receptor (S1R). However, the putative contributions of D2R and S1R to the behavioral profile of acutely administered pridopidine have not been investigated.. The present study sought to compare the effects of acute pridopidine on wild-type vs. D2R and S1R knockout mice, at high (60 mg/kg) and low (6 mg/kg) doses.. Pridopidine effects on basal and phencyclidine-induced locomotor activity was measured in the open field test. Additionally, the actions of pridopidine on prepulse inhibition was measured in animals treated with saline or phencyclidine.. Whereas inhibition of spontaneous and phencyclidine-induced locomotion was readily observed at 60 mg/kg pridopidine, neither locomotor stimulation in habituated mice, nor any effects on prepulse inhibition were detected upon pridopidine treatment. Surprisingly, inhibition of spontaneous locomotion was unaffected by both D2R and S1R deletion.. The present results suggest the involvement of additional targets, besides D2R and S1R, in mediating locomotor inhibition by pridopidine.

Topics: Acoustic Stimulation; Analysis of Variance; Animals; Dopamine Agents; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Exploratory Behavior; Locomotion; Mice; Mice, Knockout; Phencyclidine; Piperidines; Prepulse Inhibition; Receptors, Dopamine D2; Receptors, sigma; Sigma-1 Receptor; Time Factors

Pridopidine is an oral drug in clinical development for treatment of patients with Huntington's disease. This study examined the interactions of pridopidine with in vitro cytochrome P450 activity and characterized the effects of pridopidine on CYP2D6 activity in healthy volunteers using metoprolol as a probe substrate. The effect of food on pridopidine exposure was assessed.. The ability of pridopidine to inhibit and/or induce in vitro activity of drug metabolizing enzymes was examined in human liver microsomes and fresh hepatocytes. CYP2D6 inhibition potency and reversibility was assessed using dextromethorphan. For the clinical assessment, 22 healthy subjects were given metoprolol 100 mg alone and concomitantly with steady-state pridopidine 45 mg twice daily. Food effect on a single 90 mg dose of pridopidine was evaluated in a crossover manner. Safety assessments and pharmacokinetic sampling occurred throughout the study.. Pridopidine was found to be a metabolism dependent inhibitor of CYP2D6, the main enzyme catalysing its own metabolism. Flavin-containing monooxygenase heat inactivation of liver microsomes did not affect pridopidine metabolism-dependent inhibition of CYP2D6 and its inhibition of CYP2D6 was not reversible with addition of FeCN. As pridopidine is a metabolism-dependent inhibitor of CYP2D6, systemic levels of drugs metabolized by CYP2D6 may increase with chronic coadministration of pridopidine. Pridopidine can be administered without regard to food.

Topics: Area Under Curve; Cells, Cultured; Cross-Over Studies; Cytochrome P-450 CYP2D6; Cytochrome P-450 CYP2D6 Inhibitors; Dextromethorphan; Drug Interactions; Female; Ferricyanides; Food-Drug Interactions; Healthy Volunteers; Hepatocytes; Humans; Huntington Disease; Male; Metoprolol; Microsomes, Liver; Middle Aged; Piperidines

To analyze brain functional connectivity in the somatomotor and default-mode networks (DMNs) of patients with Huntington disease (HD), its relationship with gray matter (GM) volume loss, and functional changes after pridopidine treatment.. Ten patients and ten untreated controls underwent T1-weighted imaging and resting-state functional magnetic resonance imaging (fMRI); four patients were also assessed after 3 months of pridopidine treatment (90 mg/d). The seed-based functional connectivity patterns from the posterior cingulate cortex and the supplementary motor area (SMA), considered cortical hubs of the DMN and somatomotor networks, respectively, were computed. FMRIB Software Library voxel-based morphometry measured GM volume.. Patients had GM volume decrease in all cortical and subcortical areas of the somatomotor network with preservation of the SMA, and increased somatomotor and DMN connectivity. In DMN structures, functional connectivity impairment preceded volume loss. Pridopidine reduced the intensity of these aberrant connections.. The abnormal connectivity of the somatomotor and DMN observed in HD patients may represent an early dysfunction marker, as it preceded volume loss in DMN. Pridopidine reduced connectivity of these networks in all four treated patients, suggesting that connectivity is sensitive to treatment response.

Topics: Adult; Aged; Brain Mapping; Female; Gray Matter; Gyrus Cinguli; Humans; Huntingtin Protein; Huntington Disease; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; Male; Middle Aged; Models, Neurological; Motor Cortex; Neural Pathways; Oxygen; Piperidines; Rest

Pridopidine is currently under clinical development for Huntington disease (HD), with on-going studies to better characterize its therapeutic benefit and mode of action. Pridopidine was administered either prior to the appearance of disease phenotypes or in advanced stages of disease in the YAC128 mouse model of HD. In the early treatment cohort, animals received 0, 10, or 30 mg/kg pridopidine for a period of 10.5 months. In the late treatment cohort, animals were treated for 8 weeks with 0 mg/kg or an escalating dose of pridopidine (10 to 30 mg/kg over 3 weeks). Early treatment improved motor coordination and reduced anxiety- and depressive-like phenotypes in YAC128 mice, but it did not rescue striatal and corpus callosum atrophy. Late treatment, conversely, only improved depressive-like symptoms. RNA-seq analysis revealed that early pridopidine treatment reversed striatal transcriptional deficits, upregulating disease-specific genes that are known to be downregulated during HD, a finding that is experimentally confirmed herein. This suggests that pridopidine exerts beneficial effects at the transcriptional level. Taken together, our findings support continued clinical development of pridopidine for HD, particularly in the early stages of disease, and provide valuable insight into the potential therapeutic mode of action of pridopidine.

Topics: Animals; Anxiety; Behavior, Animal; Corpus Callosum; Corpus Striatum; Depression; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Evaluation, Preclinical; Female; Gene Expression Regulation; Huntington Disease; Male; Mice, Transgenic; Motor Activity; Neuroprotective Agents; Piperidines; Secondary Prevention; Transcription, Genetic

The tri-nucleotide repeat expansion underlying Huntington disease (HD) results in corticostriatal synaptic dysfunction and subsequent neurodegeneration of striatal medium spiny neurons (MSNs). HD is a devastating autosomal dominant disease with no disease-modifying treatments. Pridopidine, a postulated "dopamine stabilizer", has been shown to improve motor symptoms in clinical trials of HD. However, the target(s) and mechanism of action of pridopidine remain to be fully elucidated. As binding studies identified sigma-1 receptor (S1R) as a high-affinity receptor for pridopidine, we evaluated the relevance of S1R as a therapeutic target of pridopidine in HD. S1R is an endoplasmic reticulum - (ER) resident transmembrane protein and is regulated by ER calcium homeostasis, which is perturbed in HD. Consistent with ER calcium dysregulation, we observed striatal upregulation of S1R in aged YAC128 transgenic HD mice and HD patients. We previously demonstrated that dendritic MSN spines are lost in aged corticostriatal co-cultures from YAC128 mice. We report here that pridopidine and the chemically similar S1R agonist 3-PPP prevent MSN spine loss in aging YAC128 co-cultures. Spine protection was blocked by neuronal deletion of S1R. Pridopidine treatment suppressed supranormal ER Ca

Topics: Aging; Animals; Calbindins; Calcium; Cations, Divalent; Coculture Techniques; Corpus Striatum; Dendritic Spines; Disease Models, Animal; Endoplasmic Reticulum; Humans; Huntington Disease; Mice; Mice, Transgenic; Neuroprotective Agents; Piperidines; Rats, Inbred SHR; Receptors, sigma; Sigma-1 Receptor; Synapses

Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidine's potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25 WT mouse models. A broad, unbiased pathway analysis was conducted, followed by testing the enrichment of relevant pathways. Pridopidine upregulated the BDNF pathway (P = 1.73E-10), and its effect on BDNF secretion was sigma 1 receptor (S1R) dependent. Many of the same genes were independently found to be downregulated in Q175 KI mice compared to WT (5.2e-7 < P < 0.04). In addition, pridopidine treatment upregulated the glucocorticoid receptor (GR) response, D1R-associated genes and the AKT/PI3K pathway (P = 1E-10, P = 0.001, P = 0.004, respectively). Pridopidine upregulates expression of BDNF, D1R, GR and AKT/PI3K pathways, known to promote neuronal plasticity and survival, as well as reported to demonstrate therapeutic benefit in HD animal models. Activation of S1R, necessary for its effect on the BDNF pathway, represents a core component of the mode of action of pridopidine. Since the newly identified pathways are downregulated in neurodegenerative diseases, including HD, these findings suggest that pridopidine may exert neuroprotective effects beyond its role in alleviating some symptoms of HD.

Topics: Animals; Brain-Derived Neurotrophic Factor; Corpus Striatum; Disease Models, Animal; Gene Expression Regulation; Genome; Humans; Huntington Disease; Mice; Neuroprotective Agents; Piperidines; Rats; Receptors, Dopamine D5; Receptors, Glucocorticoid; Signal Transduction

Huntington disease (HD) is a neurodegenerative disorder for which new treatments are urgently needed. Pridopidine is a new dopaminergic stabilizer, recently developed for the treatment of motor symptoms associated with HD. The therapeutic effect of pridopidine in patients with HD has been determined in two double-blind randomized clinical trials, however, whether pridopidine exerts neuroprotection remains to be addressed. The main goal of this study was to define the potential neuroprotective effect of pridopidine, in HD in vivo and in vitro models, thus providing evidence that might support a potential disease-modifying action of the drug and possibly clarifying other aspects of pridopidine mode-of-action. Our data corroborated the hypothesis of neuroprotective action of pridopidine in HD experimental models. Administration of pridopidine protected cells from apoptosis, and resulted in highly improved motor performance in R6/2 mice. The anti-apoptotic effect observed in the in vitro system highlighted neuroprotective properties of the drug, and advanced the idea of sigma-1-receptor as an additional molecular target implicated in the mechanism of action of pridopidine. Coherent with protective effects, pridopidine-mediated beneficial effects in R6/2 mice were associated with an increased expression of pro-survival and neurostimulatory molecules, such as brain derived neurotrophic factor and DARPP32, and with a reduction in the size of mHtt aggregates in striatal tissues. Taken together, these findings support the theory of pridopidine as molecule with disease-modifying properties in HD and advance the idea of a valuable therapeutic strategy for effectively treating the disease.

Topics: Animals; Apoptosis; Brain-Derived Neurotrophic Factor; Cell Line, Transformed; Disease Models, Animal; Dopamine and cAMP-Regulated Phosphoprotein 32; Huntington Disease; Mice; Motor Activity; Neuroprotective Agents; Piperidines

Dopamine stabilizers have stimulatory actions under low dopamine tone and inhibitory actions under high dopamine tone without eliciting catalepsy. These compounds are dopamine D2 receptor (D2R) antagonists or weak partial agonists and may have pro-mnemonic and neuroprotective effects. The mechanism underlying their stimulatory and neuroprotective actions is unknown but could involve sigma-1R binding.. The present study examined sigma-1R and D2R occupancy by the dopamine stabilizer pridopidine (ACR16) at behaviorally relevant doses in living rats.. Rats were administered 3 or 15 mg/kg pridopidine, or saline, before injection of the radiotracer (11)C-SA4503 (sigma-1R) or (11)C-raclopride (D2R). Some animals received 60 mg/kg pridopidine and were only scanned with (11)C-raclopride. Cerebral (11)C-SA4503 binding was quantified using metabolite-corrected plasma input data and distribution volume (V T) calculated by Logan graphical analysis. (11)C-raclopride binding was quantified using striatum-to-cerebellum ratios and binding potentials calculated with a simplified reference tissue model.. Cunningham-Lassen plots indicated sigma-1R occupancies of 57 ± 2 and 85 ± 2% after pretreatment of animals with 3 and 15 mg/kg pridopidine. A significant (44-66%) reduction of (11)C-raclopride binding was only observed at 60 mg/kg pridopidine.. At doses shown to elicit neurochemical and behavioral effects, pridopidine occupied a large fraction of sigma-1Rs and a negligible fraction of D2Rs. Significant D2R occupancy was only observed at a dose 20-fold higher than was required for sigma-1R occupancy. The characteristics of dopamine stabilizers may result from the combination of high sigma-1R and low D2R affinity.

Topics: Animals; Carbon Radioisotopes; Dopamine Antagonists; Male; Neostriatum; Piperazines; Piperidines; Raclopride; Rats; Receptors, Dopamine D2; Receptors, sigma; Sigma-1 Receptor

Huntington disease (HD) is a chronic, genetic, neurodegenerative disease for which there is no cure. The main symptoms of HD are abnormal involuntary movements (chorea and dystonia), impaired voluntary movements (ie, incoordination and gait balance), progressive cognitive decline, and psychiatric disturbances. HD is caused by a CAG-repeat expanded mutation in the HTT gene, which encodes the huntingtin protein. The inherited mutation results in the production of an elongated polyQ mutant huntingtin protein (mHtt). The cellular functions of the Htt protein are not yet fully understood, but the functions of its mutant variant are thought to include alteration of gene transcription and energy production, and dysregulation of neurotransmitter metabolism, receptors, and growth factors. The phenylpiperidines pridopidine (4-[3-methanesulfonyl-phenyl]-1-propyl-piperidine; formerly known as ACR16) and OSU6162 ([S]-[-]-3-[3-methane [sulfonyl-phenyl]-1-propyl-piperidine) are members of a new class of pharmacologic agents known as "dopamine stabilizers". Recent clinical trials have highlighted the potential of pridopidine for symptomatic treatment of patients with HD. More recently, the analysis of HD models (ie, in vitro and in mice) highlighted previously unknown effects of pridopidine (increase in brain-derived neurotrophic factor, reduction in mHtt levels, and σ-1 receptor binding and modulation). These additional functions of pridopidine suggest it might be a neuroprotective and disease-modifying drug. Data from ongoing clinical trials of pridopidine will help define its place in the treatment of HD. This commentary examines the available preclinical and clinical evidence regarding the use of pridopidine in HD.

Topics: Animals; Dopamine; Dopamine Agents; Humans; Huntingtin Protein; Huntington Disease; Nerve Tissue Proteins; Neuroprotective Agents; Piperidines

The dopaminergic stabilizers pridopidine [4-(3-(methylsulfonyl)phenyl)-1-propylpiperidine] and ordopidine [1-ethyl-4-(2-fluoro-3-(methylsulfonyl)phenyl)piperidine] inhibit psychostimulant-induced hyperactivity, and stimulate behaviour in states of hypoactivity. While both compounds act as dopamine D2 receptor antagonists in vitro, albeit with low affinity, their specific state-dependent behavioural effect profile is not shared by D2 receptor antagonists in general. To further understand the neuropharmacological effects of pridopidine and ordopidine, and how they differ from other dopaminergic compounds in vivo, we assessed the expression of activity-regulated cytoskeleton-associated protein/activity-regulated gene 3.1 (Arc), an immediate early gene marker associated with synaptic activation, in the frontal cortex and striatum. Furthermore, monoamine neurochemistry and locomotor activity were assessed. The effects of pridopidine and ordopidine were compared to reference dopamine D1 and D2 receptor agonists and antagonists, as well as the partial dopamine D2 agonist aripiprazole. Pridopidine and ordopidine induced significant increases in cortical Arc expression, reaching 2.2- and 1.7-fold levels relative to control, respectively. In contrast, none of the reference dopamine D1 and D2 compounds tested increased cortical Arc expression. In the striatum, significant increases in Arc expression were seen with both pridopidine and ordopidine as well as the dopamine D2 receptor antagonists, remoxipride and haloperidol. Interestingly, striatal Arc expression correlated strongly and positively with striatal 3,4-dihydroxyphenylacetic acid, suggesting that antagonism of dopamine D2 receptors increases Arc expression in the striatum. In conclusion, the concurrent increase in cortical and striatal Arc expression induced by pridopidine and ordopidine appears unique for the dopaminergic stabilizers, as it was not shared by the reference compounds tested. The increase in cortical Arc expression is hypothesized to reflect enhanced N-methyl-D-aspartic acid receptor-mediated signalling in the frontal cortex, which could contribute to the state-dependent locomotor effects of pridopidine and ordopidine.

Topics: 3,4-Dihydroxyphenylacetic Acid; Analysis of Variance; Animals; Apoptosis Regulatory Proteins; Cerebral Cortex; Chromatography, High Pressure Liquid; Corpus Striatum; Dopamine; Dopamine Agents; Electrochemical Techniques; Gene Expression Regulation; Male; Motor Activity; Muscle Proteins; Piperidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Statistics as Topic

The efficacy of the dopaminergic stabilizer, pridopidine, in reducing the voluntary and involuntary motor symptoms of Huntington's disease (HD) is under clinical evaluation. Tetrabenazine is currently the only approved treatment for chorea, an involuntary motor symptom of HD; both compounds influence monoaminergic neurotransmission.. To investigate pharmacological interactions between pridopidine and tetrabenazine.. Drug-interaction experiments, supplemented by dose-response data, examined the effects of these compounds on locomotor activity, on striatal levels of dopamine and 3,4-dihydroxyphenylacetic acid (DOPAC), and on levels of activity-regulated cytoskeleton-associated (Arc) gene expression in the striatum and frontal cortex of male Sprague-Dawley rats. Haloperidol, a classical dopamine D2 receptor antagonist, was also tested for comparison.. Monitoring for 1 hour after co-administration of tetrabenazine 0.64 mg/kg and pridopidine 32 mg/kg revealed a reduction in locomotor activity, measured as distance travelled, in the tetrabenazine treated group, down to 61% vs. vehicle controls (p < 0.001). This was significantly alleviated by pridopidine (distance travelled reached 137% vs. tetrabenazine controls, p < 0.01). In contrast, co-administration of haloperidol 0.12 mg/kg and tetrabenazine produced increased inhibition of locomotor activity over the same period (p < 0.01, 41% vs. tetrabenazine). Co-administration of pridopidine, 10.5 mg/kg or 32 mg/kg, with tetrabenazine counteracted significantly (p < 0.05) and dose-dependently the decrease in frontal cortex Arc levels induced by tetrabenazine 0.64 mg/kg (Arc mRNA reached 193% vs. tetrabenazine mean at 32 mg/kg); this counteraction was not seen with haloperidol. Tetrabenazine retained its characteristic neurochemical effects of increased striatal DOPAC and reduced striatal dopamine when co-administered with pridopidine.. Pridopidine alleviates tetrabenazine-induced behavioural inhibition in rats. This effect may be associated with pridopidine-induced changes in cortical activity and may justify clinical evaluation of pridopidine/tetrabenazine combination therapy.

Topics: Animals; Behavior, Animal; Corpus Striatum; Dopamine; Dose-Response Relationship, Drug; Drug Combinations; Drug Interactions; Locomotion; Male; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Tetrabenazine; Treatment Outcome

The dopaminergic stabilizer pridopidine demonstrates state-dependent effects on locomotor activity, counteracting both hypo- and hyperactivity in rats. Pridopidine has been shown to display both functional dopamine D2 receptor antagonist properties and increase in biomarkers associated with NMDA-mediated glutamate transmission in the frontal cortex. To further characterise the effects of pridopidine on prefrontal cortex (PFC) neurons, a series of in vivo electrophysiological studies were performed in urethane-anaesthetised rats. Pridopidine, administered at doses from 10 to 60 mg/kg (i.v.), dose dependently increased pyramidal cell firing in the majority of the neurons tested. Pridopidine induced a significant increase of 162 % in mean firing activity of PFC neurons, versus initial basal firing activity as the cumulative dose of 30 mg/kg, i.v., was administered. This enhancement of activity was due to increased firing frequency of already spontaneously active neurons, rather than an increase in population activity. The increase was partially reversed or prevented by a sub-threshold dose of the dopamine D1 receptor antagonist SCH23390 (0.5 mg/kg, i.v.). Microiontophoretic application of pridopidine had only moderate activating effects. The selective dopamine D1 receptor agonist A-68930 also had limited effects when administered by microiontophoretic application, but exerted a dose dependent (0.2-3 mg/kg, i.v.) activation of firing in the majority of neurons tested (10/16). However, inhibition of firing by systemic administration of A-68930 was also observed in a subgroup of neurons (6/16). Both activation and inhibition of firing induced by systemic administration of A-68930 were reversed by the systemic administration of SCH23390. The present data suggests that pridopidine enhances pyramidal cell firing via an indirect dopamine D1 receptor-mediated mechanism. These effects of pridopidine may serve to strengthen the cortico-striatal communication and to improve motor control in Huntington's disease for which pridopidine is currently in development.

Topics: Animals; Benzazepines; Chromans; Data Interpretation, Statistical; Dopamine Agents; Dopamine Agonists; Dopamine Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Electrophysiological Phenomena; Haloperidol; Injections, Intravenous; Male; Neurons; Piperidines; Prefrontal Cortex; Pyramidal Cells; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D1

Topics: Dopamine Agents; Female; Humans; Huntington Disease; Male; Piperidines

Topics: Amphetamine; Animals; Dopamine Agents; Dose-Response Relationship, Drug; Drug Interactions; HEK293 Cells; Humans; Male; Piperidines; Protein Binding; Radioligand Assay; Rats; Rats, Sprague-Dawley; Receptors, sigma; Sigma-1 Receptor; Transfection; Tritium

Treatment-limiting motor complications occur in patients with Parkinson's disease after chronic levodopa (L-DOPA) treatment, and represent an unmet medical need. We examined the motor and neurochemical effects of the dopaminergic stabilizer pridopidine (NeuroSearch A/S, Ballerup, Denmark) in the unilateral rodent 6-OHDA lesion model, which is often used to evaluate the potential of experimental compounds for such dopamine-related motor complications. In total, 72 rats were hemi-lesioned and allocated to receive twice-daily injections of either vehicle; 6.5mg/kg L-DOPA; L-DOPA + 25 μmol/kg pridopidine; or L-DOPA + 25 μmol/kg (-)-OSU6162-a prototype dopaminergic stabilizer used previously in 6-OHDA hemi-lesion models. Animals were treated for 7, 14 or 21 days, and locomotor activity and ex vivo brain tissue neurochemistry analysed. In agreement with previous studies, L-DOPA sensitised the motor response, producing significantly more contralateral rotations than vehicle (P<0.05). Concomitant administration of pridopidine and L-DOPA significantly decreased the number of L-DOPA-induced contralateral rotations on day 7, 14 and 21 (P<0.05 versus L-DOPA alone), while still allowing a beneficial locomotor stimulant effect of L-DOPA. Concomitant pridopidine also reduced L-DOPA-induced rotation asymmetry (P<0.05 versus L-DOPA alone) and had no adverse effects on distance travelled. Brain neurochemistry was generally unaffected in all treatments groups. In conclusion, pridopidine shows potential for reducing motor complications of L-DOPA in Parkinson's disease and further testing is warranted.

Topics: Animals; Central Nervous System Sensitization; Dopamine; Dopamine Agents; Levodopa; Locomotion; Male; Oxidopamine; Piperidines; Rats; Rats, Sprague-Dawley; Rotation; Time Factors

Dopaminergic stabilizers may be conceptualized as drugs with normalizing effects on dopamine-mediated behaviours and neurochemical events. (S)-(-)-OSU6162 (OSU6162) and ACR16 are two structurally related compounds ascribed such properties, principally because of their stabilizing effects on motor activity in rodents. Reports in the literature indicate possible partial D2 receptor agonist effects using various in vitro systems. This study aimed to measure D2 receptor antagonist and agonist effects of OSU6162 and ACR16 in vivo. To address this, we have studied the effects of both compounds on prolactin secretion in drug-naive and dopamine-depleted rats; dopamine depletion was induced by pretreatment with reserpine plus α-methyl-DL: -p-tyrosine. We find that OSU6162 and ACR16 both stimulate prolactin secretion in drug-naive rats with OSU6162 being considerably more potent and efficacious. Both compounds show a non-significant trend towards reversal of the increased secretion caused by dopamine depletion, whereas the D2 receptor antagonist haloperidol further increased prolactin secretion. Thus, this study suggests that OSU6162 and ACR16 act as D2 receptor antagonists under normal conditions in vivo, possibly with minor agonist effects in a state of dopamine depletion.

Topics: Animals; Aripiprazole; Dopamine; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Haloperidol; Hyperprolactinemia; Lactotrophs; Male; Methyltyrosines; Piperazines; Piperidines; Prolactin; Quinolones; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reserpine

Topics: Female; Humans; Huntington Disease; Male; Motor Activity; Piperidines

A new pharmacological class of CNS ligands with the unique ability to stimulate or suppress motor and behavioral symptoms depending on the prevailing dopaminergic tone has been suggested as "dopaminergic stabilizers". The molecular mode-of-action of dopaminergic stabilizers is not yet fully understood, but they are assumed to act via normalization of dopaminergic signaling, through interactions with the dopamine D(2) receptor. Here we have evaluated the dopaminergic stabilizers pridopidine (ACR16) and (-)-OSU6162, as well as the new compound N-{[(2S)-5-chloro-7-(methylsulfonyl)-2,3-dihydro-1,4-benzodioxin-2-yl]methyl}ethanamine (NS30678) in a series of cellular in vitro dopamine D(2) receptor functional and binding assays. Neither ACR16, (-)-OSU6162, nor NS30678 displayed detectable dopamine D(2) receptor-mediated intrinsic activity, whereas they concentration-dependently antagonized dopamine-induced responses with IC(50) values of 12.9microM, 5.8microM, and 7.0nM, respectively. In contrast to the high-affinity typical antipsychotics haloperidol and raclopride, the dopaminergic stabilizers ACR16 and (-)-OSU6162 both displayed fast dopamine D(2) receptor dissociation properties, a feature that has previously been suggested as a contributing factor to antipsychotic atypicality and attributed mainly to low receptor affinity. However, the finding that NS30678, which is equipotent to haloperidol and raclopride, also displays fast receptor dissociation, suggests that the agonist-like structural motif of the dopaminergic stabilizers tested is a critical dissociation rate determinant. The results demonstrate that dopaminergic stabilizers exhibit fast competitive dopamine D(2) receptor antagonism, possibly allowing for temporally variable and activity-dependent dopamine D(2) receptor occupancy that may partly account for their unique stabilization of dopamine dependent behaviors in vivo.

Topics: Cell Line; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Humans; Kinetics; Ligands; Piperidines; Receptors, Dopamine D2

Modification of the partial dopamine type 2 receptor (D(2)) agonist 3-(1-benzylpiperidin-4-yl)phenol (9a) generated a series of novel functional D(2) antagonists with fast-off kinetic properties. A representative of this series, pridopidine (4-[3-(methylsulfonyl)phenyl]-1-propylpiperidine; ACR16, 12b), bound competitively with low affinity to D(2) in vitro, without displaying properties essential for interaction with D(2) in the inactive state, thereby allowing receptors to rapidly regain responsiveness. In vivo, neurochemical effects of 12b were similar to those of D(2) antagonists, and in a model of locomotor hyperactivity, 12b dose-dependently reduced activity. In contrast to classic D(2) antagonists, 12b increased spontaneous locomotor activity in partly habituated animals. The "agonist-like" kinetic profile of 12b, combined with its lack of intrinsic activity, induces a functional state-dependent D(2) antagonism that can vary with local, real-time dopamine concentration fluctuations around distinct receptor populations. These properties may contribute to its unique "dopaminergic stabilizer" characteristics, differentiating 12b from D(2) antagonists and partial D(2) agonists.

Topics: 3,4-Dihydroxyphenylacetic Acid; Animals; Binding, Competitive; Cell Line; Corpus Striatum; Dopamine; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Discovery; Drug Evaluation, Preclinical; Humans; Ligands; Male; Models, Chemical; Molecular Structure; Motor Activity; Piperazines; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

Topics: Clinical Trials, Phase III as Topic; Dopamine; Drug Evaluation, Preclinical; Humans; Huntington Disease; Movement Disorders; Piperidines

The CHDI Fifth Annual HD Therapeutics Conference, held in Palm Springs, CA, included topics covering new therapeutic developments in the field of Huntington's disease (HD). This conference report highlights presentations on biomarkers in HD; emerging topics in drug targeting, such as the lysosomal degradation pathway and target prediction by network-based modeling; understanding phenotype and neuronal circuit dysfunction in animal models; regulation of huntingtin protein expression and function; RNAi and antisense technology to deplete the mutant huntingtin protein; and small-molecule drugs that are progressing quickly through the clinic. Investigational drugs discussed include ALN-HTT (Alnylam Pharmaceuticals Inc/Medtronic Inc), EPI-743 (Edison Pharmaceuticals Inc), LNK-754 (Link Medicine Corp) and pridopidine (NeuroSearch A/S).

Topics: Animals; Biomarkers; Disease Models, Animal; Dopamine; Drug Delivery Systems; Enzyme Inhibitors; Farnesyltranstransferase; Humans; Huntingtin Protein; Huntington Disease; Leigh Disease; Lysosomes; Models, Biological; Nerve Tissue Proteins; Neurodegenerative Diseases; Nuclear Proteins; Oligonucleotides, Antisense; Phosphorylation; Piperidines; RNA, Small Interfering; Sheep; Sirtuin 1; Ubiquinone

Pridopidine (ACR16) belongs to a new pharmacological class of agents affecting the central nervous system called dopaminergic stabilizers. Dopaminergic stabilizers act primarily at dopamine type 2 (D(2)) receptors and display state-dependent behavioural effects. This article aims to give an overview of the preclinical neurochemical and behavioural in vivo pharmacological properties of pridopidine. Pridopidine was given s.c. to male Sprague-Dawley rats (locomotor, microdialysis and tissue neurochemistry) and i.p. to Swiss male mice (tail suspension test). Pridopidine dose-dependently increased striatal tissue levels of the dopamine metabolite 3,4-dihydroxyphenylalanin (ED(50)=81 micromol/kg), and prefrontal cortex dialysate levels of dopamine and noradrenaline as measured by high performance liquid chromatography. The agent reduced hyperlocomotion (d-amphetamine: ED(50)=54 micromol/kg; MK-801: ED(50)=40 micromol/kg), but preserved spontaneous locomotor activity, confirming state-dependent behavioural effects. In addition, pridopidine significantly reduced immobility time in the tail suspension test. We conclude that pridopidine state-dependently stabilizes psychomotor activity by the dual actions of functional dopamine D(2) receptor antagonism and strengthening of cortical glutamate functions in various settings of perturbed neurotransmission. The putative restoration of function in cortico-subcortical circuitry by pridopidine is likely to make it useful for ameliorating several neurological and psychiatric disorders, including Huntington's disease.

Topics: Animals; Chromatography, High Pressure Liquid; Dihydroxyphenylalanine; Dopamine; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Injections, Subcutaneous; Male; Mice; Microdialysis; Motor Activity; Norepinephrine; Piperidines; Prefrontal Cortex; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2

BACKGROUND AND PURPOSE; The two phenylpiperidines, OSU6162 and ACR16, have been proposed as novel drugs for the treatment of brain disorders, including schizophrenia and Huntington's disease, because of their putative dopamine stabilizing effects. Here we evaluated the activities of these compounds in a range of assays for the D(2) dopamine receptor in vitro.. The affinities of these compounds for the D(2) dopamine receptor were evaluated in competition with [(3) H]spiperone and [(3) H]NPA. Agonist activity of these compounds was evaluated in terms of their ability to stimulate [(35) S]GTPγS binding.. Both compounds had low affinities for inhibition of [(3) H]spiperone binding (pK(i) vs. [(3) H]spiperone, ACR16: <5, OSU6162: 5.36). Neither compound was able to stimulate [(35) S]GTPγS binding when assayed in the presence of Na(+) ions, but if the Na(+) ions were removed, both compounds were low-affinity, partial agonists (E(max) relative to dopamine: ACR16: 10.2%, OSU6162:54.3%). Schild analysis of the effects of OSU6162 to inhibit dopamine-stimulated [(35) S]GTPγS binding indicated Schild slopes of ∼0.9, suggesting little deviation from competitive inhibition. OSU6162 was, however, able to accelerate [(3) H]NPA dissociation from D(2) dopamine receptors, indicating some allosteric effects of this compound.. The two phenylpiperidines were low-affinity, low-efficacy partial agonists at the D(2) dopamine receptor in vitro, possibly exhibiting some allosteric effects. Comparing their in vitro and in vivo effects, the in vitro affinities were a reasonable guide to potencies in vivo. However, the lack of in vitro-in vivo correlation for agonist efficacy needs to be further addressed.. This article is part of a themed section on Analytical Receptor Pharmacology in Drug Discovery. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2010.161.issue-6.

Topics: Animals; CHO Cells; Cricetinae; Cricetulus; Dopamine Agonists; Humans; Piperidines; Protein Binding; Receptors, Dopamine D2

Dopaminergic stabilizers are recognized as compounds that can either enhance or antagonize dopamine (DA)-dependent behaviors depending on the prevailing dopaminergic tone. The dopaminergic stabilizer ASP2314 is being tested clinically and has been reported to have antipsychotic effects in a clinical trial as an add on medication. To elucidate the mechanisms of action of this dopaminergic stabilizer, its potency on the functional dopamine D2(High) receptors was examined. In competition with D2 receptors selectively labeled by [3H]domperidone, ASP2314 had a dissociation constant, Ki(High), of 1.62 microM for D2(High) in human cloned D2Long receptors and 0.83 muM for rat homogenized striata. Using the D2 agonist ligand [3H](+)-4-propyl-3,4,4a,5,6,10b-hexahydro-2H-naphtho[1,2-b][1,4]oxazin-9-ol ((+)PHNO), ASP2314 had a high-affinity Ki of 32 nM for D2(High) for rat homogenized striata. ASP2314 stimulated the incorporation of [35S]GTP-gamma-S into rat striata by 50% at 43 nM, and into the cloned D2Long membranes by 50% at 3.2 microM (compared to 100% stimulation by 10 microM dopamine). With similar concentrations of ASP2314 inhibiting the binding of ligands at D2(High) and stimulating [35S]GTP-gamma-S incorporation, the data indicate that the dopaminergic stabilizing action of ASP2314 may be related to the selectivity for the D2(high) state of the D2 receptor.

Topics: Animals; Binding, Competitive; Brain; CHO Cells; Cloning, Molecular; Cricetinae; Cricetulus; Dopamine; Dose-Response Relationship, Drug; Drug Interactions; Guanosine 5'-O-(3-Thiotriphosphate); Male; Piperidines; Protein Binding; Radioisotopes; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Transfection; Vitamin K 1

Dopaminergic stabilizers can be defined as drugs that stimulate or inhibit dopaminergic signalling depending on the dopaminergic tone. (-)-OSU6162 and ACR16 appear to possess such a profile. They have been proposed to act as partial dopamine receptor agonists or as antagonists with preferential action on dopaminergic autoreceptors. Previous studies have shown either stimulation or inhibition of behaviour in response to (-)-OSU6162 and ACR16, which has been suggested to reflect their dual effects on dopaminergic signalling. The aims of the present work are to (1) examine the relation between behavioural response to these drugs and activity baseline, and (2) test the suggested mechanisms of action by means of close comparisons with the known partial D2-receptor agonists (-)-3-PPP and aripiprazole, and the D2 autoreceptor preferring antagonist amisulpride with respect to effects on behaviour. From the results of these experiments it can be concluded that: (1) The direction of the response to (-)-OSU6162 and ACR16 is dependent on activity baseline, which in turn, under physiological conditions, is determined primarily by test arena size of and degree of habituation to the environment. (2) The effects of (-)-OSU6162 and ACR16 cannot be explained on the basis of either partial dopamine receptor agonism or preferential dopamine autoreceptor antagonism. Nevertheless, the current data suggest at least two different D2-receptor-associated targets which mediate opposite effects on activity. This result fits in with a mechanism proposed from a recent in vitro study, according to which (-)-OSU6162 has a dual action on dopamine D2 receptors, (a) an allosteric effect causing an enhanced response to dopamine, and (b) the previously proposed orthosteric effect antagonizing the action of dopamine.

Topics: Animals; Brain; Dopamine; Dopamine Agents; Dopamine Agonists; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Drug Interactions; Habituation, Psychophysiologic; Male; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Synaptic Transmission

"Dopamine stabilizers" are a new class of compounds that have the ability to reverse both hypo- as well as hyperdopaminergia in vivo. This class, exemplified by the phenylpiperidines (S)-(-)-3-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(-)-OSU6162] and 4-(3-methanesulfonyl-phenyl)-1-propyl)-piperidine [ACR16] although lacking high in vitro binding affinity for dopamine D2 receptor [(-)-OSU6162, Ki = 447 nM; ACR16, Ki > 1 microM], shows functional actions, suggestive of their interaction. Hence, we evaluated in vivo D2 occupancy of these agents in rats and correlated it to observed effects in a series of behavioral, neurochemical, and endocrine models relevant to the dopamine system and antipsychotic effect. Both (-)-OSU6162 and ACR16 showed robust dose-dependent striatal D2 occupancy with ED50 values of 5.27 and 18.99 mg/kg s.c., respectively, and functional assays showed no partial agonism. Over an occupancy range of 37 to 87% (3-60 mg/kg) for (-)-OSU6162 and 35 to 74% (10-60 mg/kg) for ACR16, we observed both inhibitory (amphetamine-induced locomotor activity) and stimulatory effects (in habituated rats). Haloperidol, over a similar occupancy range (33-78%), potently inhibited psychostimulant activity and induced catalepsy, but it failed to activate habituated animals. In the conditioned avoidance response assay, ACR16 was clearly more efficacious than (-)-OSU6162. In addition, both these compounds demonstrated significant preferential Fos induction in the nucleus accumbens compared with the dorsolateral striatum, a strong predictor of atypical antipsychotic efficacy. The results suggest that dopamine stabilizers exhibit locomotor stabilizing as well as antipsychotic-like effects, with low motor side effect liability, in a dose range that corresponds to high D2 in vivo occupancy.

Topics: Animals; Antipsychotic Agents; Avoidance Learning; Binding, Competitive; Dihydroxyphenylalanine; Dopamine Agents; Dopamine Antagonists; Dyskinesia, Drug-Induced; Haloperidol; Immunohistochemistry; Male; Motor Activity; Neostriatum; Nucleus Accumbens; Piperidines; Prolactin; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, Dopamine D2; Reserpine

Schizophrenia is manifested by positive and negative symptoms, as well as cognitive deficits. Most existing antipsychotic agents have poor effects on the negative symptoms of schizophrenia, thus emphasizing the necessity for developing new antipsychotic treatments. Dopaminergic stabilizers constitute one of the latest novelties in the quest for new antipsychotic drugs. Social withdrawal in rats, in response to treatment with NMDA-receptor antagonists such as (+)-MK-801, may be used to model negative symptoms. In this study we aimed to evaluate the dopaminergic stabilizers (-)-OSU6162 and ACR16, compared to haloperidol and clozapine, in a rat model for schizophrenia, focusing on (+)-MK-801 induced social withdrawal. Social behaviour and motor activity were assessed using a videotracking system, allowing automated analysis of the behaviour. Both (-)-OSU6162 and ACR16 were capable of restoring social behaviour, measured as proximity, to control level. These results indicate that these drugs may be effective in the treatments of negative symptoms.

Topics: Animals; Antipsychotic Agents; Clozapine; Dizocilpine Maleate; Dopamine; Dopamine Antagonists; Excitatory Amino Acid Antagonists; Haloperidol; Male; Motor Activity; Piperidines; Rats; Rats, Sprague-Dawley; Schizophrenic Psychology; Social Behavior

The Carlsson research group has developed a series of compounds capable of stabilising the dopamine system without inducing the deleterious hypodopaminergia that encumbers the currently used antipsychotic drugs. In the present study one of these dopaminergic stabilisers, ACR16, was tested in a mouse model for cognitive deficits of schizophrenia and autism. Since we believe that hypoglutamatergia is a key element in both schizophrenia and autism we used mice rendered hypoglutamatergic by treatment with the N-methyl-D-aspartate (NMDA) antagonist MK-801. MK-801 causes both hyperactivity and a behavioural primitivization. ACR16 attenuated the MK-801-induced hyperactivity and, in addition, caused a marked improvement of behavioural quality with a movement pattern approaching that of control animals. Since we believe that the impoverishment of the behavioural repertoire caused by MK-801 may correspond to the cognitive deficits seen in schizophrenia and autism, these results suggest that ACR16 may improve cognitive status in these disorders.

Topics: Animals; Autistic Disorder; Behavior, Animal; Cognition; Dizocilpine Maleate; Dopamine Antagonists; Dopamine D2 Receptor Antagonists; Dose-Response Relationship, Drug; Excitatory Amino Acid Antagonists; Glutamic Acid; Grooming; Haloperidol; Hyperkinesis; Male; Mice; Motor Activity; Piperidines; Schizophrenia