Pridopidine

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Pridopidine
Pridopidine.svg
Identifiers
  • 4-(3-methylsulfonylphenyl)-1-propylpiperidine
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.240.998 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C15H23NO2S
Molar mass 281.41 g·mol−1
3D model (JSmol)
  • CCCN1CCC(CC1)C2=CC(=CC=C2)S(=O)(=O)C
  • 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
  • Key:YGKUEOZJFIXDGI-UHFFFAOYSA-N

Pridopidine (also known as PL-101) is an orally administrated small molecule investigational drug. Pridopidine is a selective and potent Sigma-1 Receptor agonist. It is being developed by Prilenia Therapeutics and is currently in late-stage clinical development for Huntington's disease (HD) and amyotrophic lateral sclerosis (ALS).

Contents

Mechanism of action

Pridopidine works by binding and activating an intracellular protein called the Sigma-1 receptor (S1R) located at the mitochondria-associated membrane (MAM) of the endoplasmic reticulum (ER). The S1R regulates key cellular processes crucial to neuronal health and survival. Selective activation of the S1R is a promising therapeutic target for treating neurodegenerative and neurodevelopmental disorders.

Pridopidine activation of the S1R demonstrates neuroprotective effects in numerous models of neurodegenerative diseases including HD, ALS, Glaucoma, Parkinson's disease (PD) and Alzheimer's disease (AD). [1] [2] [3]  

Pridopidine exhibits a neuroprotective effect against mutant Huntingtin (mHTT)-induced cell death in mouse primary HD neurons and human HD iPSCs. [4] It restores the impaired synaptic plasticity in HD neurons, [5] enhances mitochondrial function, [6] upregulates BDNF transport and secretion, reduces ER stress and restores dendritic spine abnormalities in HD and AD models. [7] [8] [9] [10] In models of ALS, pridopidine protects neuron-muscle connectivity and restores muscle integrity and contractility. [1] These beneficial effects are exclusively mediated by the S1R as either deletion of this gene, or selective inhibition of its function, completely abolish pridopidine's beneficial effects.

Initially, the primary target of pridopidine was postulated to be the dopamine D2/D3 receptors. However, in-vitro binding assays show that pridopidine has high affinity for the S1R and low affinity for other targets including the dopamine D2/D3 receptors, adrenergic a2C receptor and the Sigma-2 receptor. [11] Furthermore, selective and robust occupancy of the S1R, with no or negligible occupancy of the D2/D3 receptors was demonstrated by in-vivo positron emission tomography (PET) imaging studies in rats and human. [12] [13]

Potential indications

Huntington's disease (HD)

HD is a progressive fatal neurodegenerative disease caused by a mutation in the Huntingtin gene (expanded CAG repeat >35). The disease is characterized by progressive motor abnormalities, cognitive decline, and psychiatric and behavioral symptoms. [14] Adult-onset HD usually begins between 35 and 45 years of age. Following onset, motor, cognitive and functional outcomes steadily decline over 15 to 20 years, ultimately leading to a state of profound incapacity and death. The disease is inherited in an autosomal dominant manner, and thus each child of a parent with HD has a 50% chance of inheriting the mutated HD gene. [15] For patients and their families, maintaining functional capacity is vital as it translates to a patient's ability to maintain their occupation, continue to manage their daily lives, and live independently. [16] [17]

A meta-analysis of four randomized controlled trials (RCTs) involving 1,130 patients (816 in the pridopidine group and 314 in the placebo group) found that pridopidine led to a slight, though not statistically significant, improvement in overall motor symptoms, as measured by the Unified Huntington's Disease Rating Scale Total Motor Score, compared to placebo. However, the drug significantly improved voluntary movements, as indicated by the Modified Motor Score. [18] Pridopidine was generally well tolerated, with no significant differences in adverse events or serious adverse events compared to placebo. The findings suggest that pridopidine has potential for treating motor symptoms in HD, with a favorable safety profile, warranting further clinical trials to confirm its benefits. [18]

Amyotrophic lateral sclerosis

ALS is a devastating progressive fatal neurodegenerative disease characterized by upper and lower motor neuron degeneration. Over time this progressive loss of motor function leads to losing the ability to speak, eat, move and eventually breathe. [19]

In 2019, pridopidine was selected by the Sean M. Healey & AMG Center for ALS at the Massachusetts General Hospital as one of the first potential new innovative treatments to be evaluated in the first Platform Trial in ALS [19] −, [20] aimed to  accelerate clinical trials in ALS. The first patient in the pridopidine regimen was enrolled in December 2020 (NCT04615923). The study will enroll 160 patients in each regimen with a 3:1 randomization (120 patients to be treated with pridopidine and 40 patients treated with placebo, daily for 24 weeks).

Related Research Articles

<span class="mw-page-title-main">Huntington's disease</span> Inherited neurodegenerative disorder

Huntington's disease (HD), also known as Huntington's chorea, is an incurable neurodegenerative disease that is mostly inherited. The earliest symptoms are often subtle problems with mood or mental/psychiatric abilities. A general lack of coordination and an unsteady gait often follow. It is also a basal ganglia disease causing a hyperkinetic movement disorder known as chorea. As the disease advances, uncoordinated, involuntary body movements of chorea become more apparent. Physical abilities gradually worsen until coordinated movement becomes difficult and the person is unable to talk. Mental abilities generally decline into dementia, depression, apathy, and impulsivity at times. The specific symptoms vary somewhat between people. Symptoms usually begin between 30 and 50 years of age, and can start at any age but are usually seen around the age of 40. The disease may develop earlier in each successive generation. About eight percent of cases start before the age of 20 years, and are known as juvenile HD, which typically present with the slow movement symptoms of Parkinson's disease rather than those of chorea.

<span class="mw-page-title-main">Nucleus accumbens</span> Region of the basal forebrain

The nucleus accumbens is a region in the basal forebrain rostral to the preoptic area of the hypothalamus. The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum. The ventral striatum and dorsal striatum collectively form the striatum, which is the main component of the basal ganglia. The dopaminergic neurons of the mesolimbic pathway project onto the GABAergic medium spiny neurons of the nucleus accumbens and olfactory tubercle. Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

<span class="mw-page-title-main">Dopamine receptor</span> Class of G protein-coupled receptors

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

<span class="mw-page-title-main">Neuroprotection</span> Relative preservation of neurons

Neuroprotection refers to the relative preservation of neuronal structure and/or function. In the case of an ongoing insult the relative preservation of neuronal integrity implies a reduction in the rate of neuronal loss over time, which can be expressed as a differential equation.

<span class="mw-page-title-main">Huntingtin</span> Gene and protein involved in Huntingtons disease

Huntingtin(Htt) is the protein coded for in humans by the HTT gene, also known as the IT15 ("interesting transcript 15") gene. Mutated HTT is the cause of Huntington's disease (HD), and has been investigated for this role and also for its involvement in long-term memory storage.

<span class="mw-page-title-main">Pramipexole</span> Dopamine agonist medication

Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). In Parkinson's disease it may be used alone or together with levodopa. It is taken by mouth. Pramipexole is a dopamine agonist of the non-ergoline class.

<span class="mw-page-title-main">Neurodegenerative disease</span> Central nervous system disease

A neurodegenerative disease is caused by the progressive loss of neurons, in the process known as neurodegeneration. Neuronal damage may also ultimately result in their death. Neurodegenerative diseases include amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, Alzheimer's disease, Huntington's disease, multiple system atrophy, tauopathies, and prion diseases. Neurodegeneration can be found in the brain at many different levels of neuronal circuitry, ranging from molecular to systemic.Because there is no known way to reverse the progressive degeneration of neurons, these diseases are considered to be incurable; however research has shown that the two major contributing factors to neurodegeneration are oxidative stress and inflammation. Biomedical research has revealed many similarities between these diseases at the subcellular level, including atypical protein assemblies and induced cell death. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well.

<span class="mw-page-title-main">Medium spiny neuron</span> Type of GABAergic neuron in the striatum

Medium spiny neurons (MSNs), also known as spiny projection neurons (SPNs), are a special type of inhibitory GABAergic neuron representing approximately 90% of neurons within the human striatum, a basal ganglia structure. Medium spiny neurons have two primary phenotypes : D1-type MSNs of the direct pathway and D2-type MSNs of the indirect pathway. Most striatal MSNs contain only D1-type or D2-type dopamine receptors, but a subpopulation of MSNs exhibit both phenotypes.

<span class="mw-page-title-main">Latrepirdine</span> Antihistamine drug

Latrepirdine is an antihistamine drug which has been used clinically in Russia since 1983.

<span class="mw-page-title-main">Istradefylline</span> Chemical compound

Istradefylline, sold under the brand name Nourianz, is a medication used as an add-on treatment to levodopa/carbidopa in adults with Parkinson's disease (PD) experiencing "off" episodes. Istradefylline reduces "off" periods resulting from long-term treatment with the antiparkinson drug levodopa. An "off" episode is a time when a patient's medications are not working well, causing an increase in PD symptoms, such as tremor and difficulty walking.

<span class="mw-page-title-main">Blonanserin</span> Atypical antipsychotic

Blonanserin, sold under the brand name Lonasen, is a relatively new atypical antipsychotic commercialized by Dainippon Sumitomo Pharma in Japan and Korea for the treatment of schizophrenia. Relative to many other antipsychotics, blonanserin has an improved tolerability profile, lacking side effects such as extrapyramidal symptoms, excessive sedation, or hypotension. As with many second-generation (atypical) antipsychotics it is significantly more efficacious in the treatment of the negative symptoms of schizophrenia compared to first-generation (typical) antipsychotics such as haloperidol.

<span class="mw-page-title-main">Basal ganglia disease</span> Group of physical problems resulting from basal ganglia dysfunction

Basal ganglia disease is a group of physical problems that occur when the group of nuclei in the brain known as the basal ganglia fail to properly suppress unwanted movements or to properly prime upper motor neuron circuits to initiate motor function. Research indicates that increased output of the basal ganglia inhibits thalamocortical projection neurons. Proper activation or deactivation of these neurons is an integral component for proper movement. If something causes too much basal ganglia output, then the ventral anterior (VA) and ventral lateral (VL) thalamocortical projection neurons become too inhibited, and one cannot initiate voluntary movement. These disorders are known as hypokinetic disorders. However, a disorder leading to abnormally low output of the basal ganglia leads to reduced inhibition, and thus excitation, of the thalamocortical projection neurons which synapse onto the cortex. This situation leads to an inability to suppress unwanted movements. These disorders are known as hyperkinetic disorders.

<span class="mw-page-title-main">Ecopipam</span> Investigational dopamine antagonist

Ecopipam is a dopamine antagonist which is under development for the treatment of Lesch-Nyhan syndrome, Tourette syndrome, speech disorders, and restless legs syndrome. It is taken by mouth.

<span class="mw-page-title-main">Cariprazine</span> Atypical antipsychotic medicine

Cariprazine, sold under the brand name Vraylar among others, is an atypical antipsychotic developed by Gedeon Richter, which is used in the treatment of schizophrenia, bipolar mania, bipolar depression, and major depressive disorder. It acts primarily as a D3 and D2 receptor partial agonist, with a preference for the D3 receptor. Cariprazine is also a partial agonist at the serotonin 5-HT1A receptor and acts as an antagonist at 5-HT2B and 5-HT2A receptors, with high selectivity for the D3 receptor. It is taken by mouth.

<span class="mw-page-title-main">OSU-6162</span> Chemical compound

OSU-6162 (PNU-96391) is a compound which acts as a partial agonist at both dopamine D2 receptors and 5-HT2A receptors. It acts as a dopamine stabilizer in a similar manner to the closely related drug pridopidine, and has antipsychotic, anti-addictive and anti-Parkinsonian effects in animal studies. Both enantiomers show similar activity but with different ratios of effects, with the (S) enantiomer (–)-OSU-6162 that is more commonly used in research, having higher binding affinity to D2 but is a weaker partial agonist at 5-HT2A, while the (R) enantiomer (+)-OSU-6162 has higher efficacy at 5-HT2A but lower D2 affinity.

<span class="mw-page-title-main">Brexpiprazole</span> Atypical antipsychotic

Brexpiprazole, sold under the brand name Rexulti among others, is an atypical antipsychotic medication used for the treatment of major depressive disorder, schizophrenia, and agitation associated with dementia due to Alzheimer's disease.

<span class="mw-page-title-main">Estrogen and neurodegenerative diseases</span>

Neurodegenerative diseases can disrupt the normal human homeostasis and result in abnormal estrogen levels. For example, neurodegenerative diseases can cause different physiological effects in males and females. In particular, estrogen studies have revealed complex interactions with neurodegenerative diseases. Estrogen was initially proposed to be a possible treatment for certain types of neurodegenerative diseases but a plethora of harmful side effects such as increased susceptibility to breast cancer and coronary heart disease overshadowed any beneficial outcomes. On the other hand, Estrogen Replacement Therapy has shown some positive effects with postmenopausal women. Estrogen and estrogen-like molecules form a large family of potentially beneficial alternatives that can have dramatic effects on human homeostasis and disease. Subsequently, large-scale efforts were initiated to screen for useful estrogen family molecules. Furthermore, scientists discovered new ways to synthesize estrogen-like compounds that can avoid many side effects.

<span class="mw-page-title-main">Bernhard Landwehrmeyer</span> German neurologist and neuroscientist (born 1960)

Georg Bernhard Landwehrmeyer FRCP is a German neurologist and neuroscientist in the field of neurodegeneration primarily focusing on Huntington's disease. Landwehrmeyer is a professor of neurology at Ulm University Hospital. He was one of the founders of the European Huntington's Disease Network (EHDN) in 2004 and was chairman of its executive committee until 2014.

Emma Louise Scotter is a New Zealand academic neuropharmacologist, and is a senior lecturer at the University of Auckland, and head of the university's Centre for Brain Research. In 2024 she was appointed a Member of the New Zealand Order of Merit for services to Motor Neuron Disease research.

References

  1. 1 2 Ionescu A, Gradus T, Altman T, Maimon R, Saraf Avraham N, Geva M, et al. (March 2019). "Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1G93A Model". Cell Death & Disease. 10 (3): 210. doi:10.1038/s41419-019-1451-2. PMC   6397200 . PMID   30824685.
  2. ↑ Geva M, Gershoni-Emek N, Naia L, Ly P, Mota S, Rego AC, et al. (November 2021). "Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma". Scientific Reports. 11 (1): 21975. Bibcode:2021NatSR..1121975G. doi:10.1038/s41598-021-01077-w. PMC   8578336 . PMID   34753986.
  3. ↑ Francardo V, Geva M, Bez F, Denis Q, Steiner L, Hayden MR, et al. (April 2019). "Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease". Neurotherapeutics. 16 (2): 465–479. doi:10.1007/s13311-018-00699-9. PMC   6554374 . PMID   30756361.
  4. ↑ Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, Ross CA (September 2019). "Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor". Neurobiology of Disease. 129: 118–129. doi:10.1016/j.nbd.2019.05.009. PMC   6996243 . PMID   31108174.
  5. ↑ Smith-Dijak AI, Nassrallah WB, Zhang LY, Geva M, Hayden MR, Raymond LA (2019). "Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease". Frontiers in Cellular Neuroscience. 13: 209. doi: 10.3389/fncel.2019.00209 . PMC   6532531 . PMID   31156395.
  6. ↑ Naia L, Ly P, Mota SI, Lopes C, Maranga C, Coelho P, et al. (April 2021). "The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models". Neurotherapeutics. 18 (2): 1017–1038. doi:10.1007/s13311-021-01022-9. PMC   8423985 . PMID   33797036.
  7. ↑ Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, et al. (January 2017). "The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease". Neurobiology of Disease. 97 (Pt A): 46–59. doi:10.1016/j.nbd.2016.10.006. PMC   5214572 . PMID   27818324.
  8. ↑ Ryskamp D, Wu L, Wu J, Kim D, Rammes G, Geva M, et al. (April 2019). "Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor". Neurobiology of Disease. 124: 489–504. doi:10.1016/j.nbd.2018.12.022. PMC   6363865 . PMID   30594810.
  9. ↑ Shenkman M, Geva M, Gershoni-Emek N, Hayden MR, Lederkremer GZ (July 2021). "Pridopidine reduces mutant huntingtin-induced endoplasmic reticulum stress by modulation of the Sigma-1 receptor". Journal of Neurochemistry. 158 (2): 467–481. doi: 10.1111/jnc.15366 . PMID   33871049. S2CID   233300408.
  10. ↑ Geva M, Kusko R, Soares H, Fowler KD, Birnberg T, Barash S, et al. (September 2016). "Pridopidine activates neuroprotective pathways impaired in Huntington Disease". Human Molecular Genetics. 25 (18): 3975–3987. doi:10.1093/hmg/ddw238. PMC   5291233 . PMID   27466197.
  11. ↑ Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savola JM, et al. (May 2019). "Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques". Movement Disorders. 34 (5): 708–716. doi:10.1002/mds.27565. PMID   30575996. S2CID   58587757.
  12. ↑ Grachev ID, Meyer PM, Becker GA, Bronzel M, Marsteller D, Pastino G, et al. (April 2021). "Sigma-1 and dopamine D2/D3 receptor occupancy of pridopidine in healthy volunteers and patients with Huntington disease: a [18F] fluspidine and [18F] fallypride PET study". European Journal of Nuclear Medicine and Molecular Imaging. 48 (4): 1103–1115. doi:10.1007/s00259-020-05030-3. PMC   8041674 . PMID   32995944.
  13. ↑ Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, et al. (September 2015). "Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses". Psychopharmacology. 232 (18): 3443–3453. doi:10.1007/s00213-015-3997-8. PMC   4537502 . PMID   26159455.
  14. ↑ McColgan P, Tabrizi SJ (January 2018). "Huntington's disease: a clinical review". European Journal of Neurology. 25 (1): 24–34. doi: 10.1111/ene.13413 . PMID   28817209. S2CID   24764480.
  15. ↑ "A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group". Cell. 72 (6): 971–983. March 1993. doi:10.1016/0092-8674(93)90585-e. hdl: 2027.42/30901 . PMID   8458085. S2CID   802885.
  16. ↑ Huntington Study Group (March 1996). "Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group". Movement Disorders. 11 (2): 136–142. doi:10.1002/mds.870110204. PMID   8684382. S2CID   45982731.
  17. ↑ "Huntington's Disease" (PDF). Center for Drug Evaluation and Research (CDER). The Voice of the Patient: A series of reports from the FDA’s Patient-Focused Drug Development Initiative. U.S. Food and Drug Administration (FDA). March 2016. Archived from the original (PDF) on 16 March 2022.
  18. 1 2 Asla MM, Nawar AA, Abdelsalam A, Elsayed E, Rizk MA, Hussein MA, et al. (January 2022). "The Efficacy and Safety of Pridopidine on Treatment of Patients with Huntington's Disease: A Systematic Review and Meta-Analysis". Movement Disorders Clinical Practice. 9 (1): 20–30. doi:10.1002/mdc3.13357. PMC   8721839 . PMID   35005061.
  19. 1 2 Verma A (2021-07-25). "Clinical Manifestation and Management of Amyotrophic Lateral Sclerosis". In Araki T (ed.). Amyotrophic Lateral Sclerosis. Exon Publications. pp. 1–14. doi:10.36255/exonpublications.amyotrophiclateralsclerosis.management.2021. ISBN   978-0-645-00177-8. PMID   34473441. S2CID   237727438.
  20. ↑ "Sean M. Healey & AMG Center for ALS at Mass General launches first ALS Platform Trial with 5 promising drugs". Massachusetts General Hospital. Retrieved 2021-12-06.
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