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| ln Vitro |
Dopamine (DA) stabilizer pridopidine has the potential to act as a neuroprotective neuromodulator in patients with Huntington's disease (HD). In order to assess pridopidine's neuroprotective effectiveness and investigate the underlying molecular pathways, it was determined whether pridopidine might prevent cell death and eventually activate targets that promote survival. In immortalized striatal knock-in cells expressing natural amounts of mutant Htt (STHdh111/111), administration of the most effective dose of pridopidine (150 μM) greatly reduced apoptosis and significantly improved the pro-survival kinase ERK phosphorylation state [2].
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| ln Vivo |
It is known that pridipidine functions as a low affinity D2R antagonist. The binding of pridopidine to the endoplasmic reticulum (ER) sigma 1 receptor (S1R) may be the cause of its action. In order to bolster the theory that S1R activation upregulates the BDNF pathway, SD rats were administered lower dosages of pridopidine (0.3–60 mg/kg), and qPCR was used to assess the expression of seven chosen BDNF pathway genes. According to in vivo PET imaging, rats given dosages of 3 mg/kg and 15 mg/kg of pridipidine occupied 57±2% and 85±2% of the S1R, respectively, and neither demonstrated occupancy of the D2R. D2R only showed significant occupancy (44-66%) at the dose of 60 mg/kg. The conclusion that gene upregulation in rats treated with 15 mg/kg pridopidine is due to S1R-specific activation is supported by this PET investigation. S1R is saturated at 30 mg/kg, and partial/low occupancy of D2R is between 22 and 33% (assuming linearity). Indeed, qPCR research revealed that the expression of CDNK1A and CEBPB increased from 15 mg/kg to 15 mg/kg, and the expression of EGR2, HOMER1A, KLF5, and ARC was up-regulated at the low dose of 15 mg/kg. EGR1 was also up-regulated, up to 3 mg/kg. markedly elevated at low concentrations. CEBPB increased significantly at 3 mg/kg but not at 15 mg/kg at the low dose of 30 mg/kg [1]. Preclinical research has been done in R6/2 mice to further validate pridopidine's advantageous effects on the HD motor phenotype and to clarify whether pridopidine may also function as a neuroprotective drug. In R6/2 mice, pridipidine administered daily at the most beneficial dosage of 5 mg/kg avoids both acute and common progressive motor deterioration and greatly retains motor function. The mice continued to benefit from pridopidine for about 4 weeks, at which point their performance on the horizontal ladder exercise and in the open field somewhat declined. Furthermore, Kaplan-Meier survival curve analysis revealed that pridopidine significantly increased the mice's longevity [2].
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| Animal Protocol |
10-Day Gene Expression Study:** Male Sprague Dawley rats (n=6 per group) were treated daily by oral gavage with Pridopidine HCl (60 mg/kg) dissolved in sterile ddH₂O or vehicle (sterile ddH₂O) for 10 days. On day 10, 90 minutes after the final dose, brains were removed. The striatum from the left hemisphere was extracted, placed in RNAlater solution, and stored for RNA isolation and subsequent gene expression analysis (microarray and qPCR). This dose was chosen as it was consistently efficacious in reducing motor activity in hyperactive rats. [1]
- **5-Day Dose-Range Study:** Male Sprague Dawley rats were divided into 6 groups (n=10 per group) and treated daily by oral gavage with Pridopidine at doses of 0.3, 3, 15, 30, 60 mg/kg or vehicle for five days. On day 5, 90 minutes after the final dose, brains were removed, and striatal tissue was processed for qPCR analysis to confirm gene expression changes. [1] |
| References |
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| Additional Infomation |
ACR-16 is currently being investigated by NeuroSearch. ACR-16 has been successfully studied in a Phase II, multicenter, randomized, placebo-controlled trial in patients with Huntington's disease, and three Phase Ib studies are underway in patients with Huntington's disease, Parkinson's disease, and schizophrenia. ACR-16 is a dopamine stabilizer. ACR-16 is also being investigated for other mental and neurological disorders. Pridopidine is already in clinical trials for the treatment of Huntington's disease. [hr>Drug Indications
Investigated for the treatment of Huntington's disease, schizophrenia, and schizoaffective disorder.] [hr>Mechanism of Action ACR-16 belongs to a new class of drugs characterized by dopaminergic stabilizers, which are centrally active compounds that enhance or antagonize dopaminergic effects in the brain depending on the initial level of dopaminergic activity. ACR-16 works by "modulating" multiple functions of this neurotransmitter in the striatum and other brain regions.] Therefore, they can stabilize behavioral and motor disorders caused by neurological and psychiatric illnesses. They function in the pathological state without impairing normal thought processes or motor functions. |
| Molecular Formula |
C14H20FNO2S
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|---|---|
| Molecular Weight |
285.3774
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| Exact Mass |
281.145
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| CAS # |
346688-38-8
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| PubChem CID |
9795739
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| Appearance |
White to off-white solid powder
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| Density |
1.093g/cm3
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| Boiling Point |
434.205ºC at 760 mmHg
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| Melting Point |
73-75ºC
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| Flash Point |
216.4ºC
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| Index of Refraction |
1.526
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| LogP |
3.698
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
4
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| Heavy Atom Count |
19
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| Complexity |
366
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| Defined Atom Stereocenter Count |
0
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| SMILES |
S(C([H])([H])[H])(C1=C([H])C([H])=C([H])C(=C1[H])C1([H])C([H])([H])C([H])([H])N(C([H])([H])C([H])([H])C([H])([H])[H])C([H])([H])C1([H])[H])(=O)=O
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| InChi Key |
YGKUEOZJFIXDGI-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C15H23NO2S/c1-3-9-16-10-7-13(8-11-16)14-5-4-6-15(12-14)19(2,17)18/h4-6,12-13H,3,7-11H2,1-2H3
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| Chemical Name |
4-(3-methylsulfonylphenyl)-1-propylpiperidine
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| Synonyms |
ACR16 ACR-16 ACR 16 ACR16 compound PridopidineFR-310826 FR 310826 FR310826
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
DMSO : ~100 mg/mL (~355.35 mM)
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| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.5 mg/mL (8.88 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.5 mg/mL (8.88 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (8.88 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.5041 mL | 17.5205 mL | 35.0410 mL | |
| 5 mM | 0.7008 mL | 3.5041 mL | 7.0082 mL | |
| 10 mM | 0.3504 mL | 1.7520 mL | 3.5041 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
| NCT Number | Recruitment | interventions | Conditions | Sponsor/Collaborators | Start Date | Phases |
| NCT06069934 | AVAILABLE | Drug: Pridopidine | Amyotrophic Lateral Sclerosis | Prilenia | ||
| NCT04615923 | COMPLETEDWITH RESULTS | Drug: Pridopidine Drug: Matching Placebo |
Amyotrophic Lateral Sclerosis | Merit E. Cudkowicz, MD | 2020-12-18 | Phase 2 Phase 3 |
| NCT02494778 | TERMINATEDWITH RESULTS | Drug: Pridopidine | Huntington's Disease | Prilenia | 2015-09-24 | Phase 2 |
| NCT01306929 | COMPLETEDWITH RESULTS | Drug: pridopidine | Huntington Disease | Prilenia | 2011-03-24 | Phase 2 |
| NCT04556656 | ACTIVE, NOT RECRUITING | Drug: Pridopidine Drug: Placebo |
Huntington Disease | Prilenia | 2020-10-16 | Phase 3 |
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