Pridopidine

{{Short description|Chemical compound}} {{Distinguish|Prodipine}} {{Use dmy dates|date=December 2024}} {{cs1 config|nae-list-style=vanc|display-authors=6}} {{Infobox drug | image = Pridopidine.svg | image_class = skin-invert-image | width = | alt = | caption =

| legal_status =

| IUPAC_name = 4-(3-methylsulfonylphenyl)-1-propylpiperidine | C=15 | H=23 | N=1 | O=2 | S=1 | SMILES = CCCN1CCC(CC1)C2=CC(=CC=C2)S(=O)(=O)C | StdInChI = 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 | StdInChIKey = YGKUEOZJFIXDGI-UHFFFAOYSA-N }}

'''Pridopidine''' (developmental code name '''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).

== 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. 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).<ref name="Ionescu_2019">{{cite journal | vauthors = Ionescu A, Gradus T, Altman T, Maimon R, Saraf Avraham N, Geva M, Hayden M, Perlson E | title = Targeting the Sigma-1 Receptor via Pridopidine Ameliorates Central Features of ALS Pathology in a SOD1G93A Model | journal = Cell Death & Disease | volume = 10 | issue = 3 | pages = 210 | date = March 2019 | pmid = 30824685 | pmc = 6397200 | doi = 10.1038/s41419-019-1451-2 }}</ref><ref>{{cite journal | vauthors = Geva M, Gershoni-Emek N, Naia L, Ly P, Mota S, Rego AC, Hayden MR, Levin LA | title = Neuroprotection of retinal ganglion cells by the sigma-1 receptor agonist pridopidine in models of experimental glaucoma | journal = Scientific Reports | volume = 11 | issue = 1 | pages = 21975 | date = November 2021 | pmid = 34753986 | pmc = 8578336 | doi = 10.1038/s41598-021-01077-w | bibcode = 2021NatSR..1121975G }}</ref><ref>{{cite journal | vauthors = Francardo V, Geva M, Bez F, Denis Q, Steiner L, Hayden MR, Cenci MA | title = Pridopidine Induces Functional Neurorestoration Via the Sigma-1 Receptor in a Mouse Model of Parkinson's Disease | journal = Neurotherapeutics | volume = 16 | issue = 2 | pages = 465–479 | date = April 2019 | pmid = 30756361 | pmc = 6554374 | doi = 10.1007/s13311-018-00699-9 }}</ref>

Pridopidine exhibits a neuroprotective effect against mutant Huntingtin (mHTT)-induced cell death in mouse primary HD neurons and human HD-induced pluripotent stem cells.<ref>{{cite journal | vauthors = Eddings CR, Arbez N, Akimov S, Geva M, Hayden MR, Ross CA | title = Pridopidine protects neurons from mutant-huntingtin toxicity via the sigma-1 receptor | journal = Neurobiology of Disease | volume = 129 | pages = 118–129 | date = September 2019 | pmid = 31108174 | pmc = 6996243 | doi = 10.1016/j.nbd.2019.05.009 }}</ref> It restores the impaired synaptic plasticity in HD neurons,<ref>{{cite journal | vauthors = Smith-Dijak AI, Nassrallah WB, Zhang LY, Geva M, Hayden MR, Raymond LA | title = Impairment and Restoration of Homeostatic Plasticity in Cultured Cortical Neurons From a Mouse Model of Huntington Disease | journal = Frontiers in Cellular Neuroscience | volume = 13 | pages = 209 | date = 2019 | pmid = 31156395 | pmc = 6532531 | doi = 10.3389/fncel.2019.00209 | doi-access = free }}</ref> enhances mitochondrial function,<ref>{{cite journal | vauthors = Naia L, Ly P, Mota SI, Lopes C, Maranga C, Coelho P, Gershoni-Emek N, Ankarcrona M, Geva M, Hayden MR, Rego AC | title = The Sigma-1 Receptor Mediates Pridopidine Rescue of Mitochondrial Function in Huntington Disease Models | journal = Neurotherapeutics | volume = 18 | issue = 2 | pages = 1017–1038 | date = April 2021 | pmid = 33797036 | pmc = 8423985 | doi = 10.1007/s13311-021-01022-9 }}</ref> upregulates BDNF transport and secretion, reduces endoplasmic reticulum stress and restores dendritic spine abnormalities in HD and AD models.<ref>{{cite journal | vauthors = Ryskamp D, Wu J, Geva M, Kusko R, Grossman I, Hayden M, Bezprozvanny I | title = The sigma-1 receptor mediates the beneficial effects of pridopidine in a mouse model of Huntington disease | journal = Neurobiology of Disease | volume = 97 | issue = Pt A | pages = 46–59 | date = January 2017 | pmid = 27818324 | pmc = 5214572 | doi = 10.1016/j.nbd.2016.10.006 }}</ref><ref name="Ryskamp 489–504">{{cite journal | vauthors = Ryskamp D, Wu L, Wu J, Kim D, Rammes G, Geva M, Hayden M, Bezprozvanny I | title = Pridopidine stabilizes mushroom spines in mouse models of Alzheimer's disease by acting on the sigma-1 receptor | journal = Neurobiology of Disease | volume = 124 | pages = 489–504 | date = April 2019 | pmid = 30594810 | pmc = 6363865 | doi = 10.1016/j.nbd.2018.12.022 }}</ref><ref>{{cite journal | vauthors = Shenkman M, Geva M, Gershoni-Emek N, Hayden MR, Lederkremer GZ | title = Pridopidine reduces mutant huntingtin-induced endoplasmic reticulum stress by modulation of the Sigma-1 receptor | journal = Journal of Neurochemistry | volume = 158 | issue = 2 | pages = 467–481 | date = July 2021 | pmid = 33871049 | doi = 10.1111/jnc.15366 | s2cid = 233300408 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Geva M, Kusko R, Soares H, Fowler KD, Birnberg T, Barash S, -Wagner AM, Fine T, Lysaght A, Weiner B, Cha Y, Kolitz S, Towfic F, Orbach A, Laufer R, Zeskind B, Grossman I, Hayden MR | title = Pridopidine activates neuroprotective pathways impaired in Huntington Disease | journal = Human Molecular Genetics | volume = 25 | issue = 18 | pages = 3975–3987 | date = September 2016 | pmid = 27466197 | pmc = 5291233 | doi = 10.1093/hmg/ddw238 }}</ref> In models of ALS, pridopidine protects neuron-muscle connectivity and restores muscle integrity and contractility.<ref name="Ionescu_2019" /> 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.<ref>{{cite journal | vauthors = Johnston TH, Geva M, Steiner L, Orbach A, Papapetropoulos S, Savola JM, Reynolds IJ, Ravenscroft P, Hill M, Fox SH, Brotchie JM, Laufer R, Hayden MR | title = Pridopidine, a clinic-ready compound, reduces 3,4-dihydroxyphenylalanine-induced dyskinesia in Parkinsonian macaques | journal = Movement Disorders | volume = 34 | issue = 5 | pages = 708–716 | date = May 2019 | pmid = 30575996 | doi = 10.1002/mds.27565 | s2cid = 58587757 }}</ref> 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.<ref name="Grachev 1103–1115">{{cite journal | vauthors = Grachev ID, Meyer PM, Becker GA, Bronzel M, Marsteller D, Pastino G, Voges O, Rabinovich L, Knebel H, Zientek F, Rullmann M, Sattler B, Patt M, Gerhards T, Strauss M, Kluge A, Brust P, Savola JM, Gordon MF, Geva M, Hesse S, Barthel H, Hayden MR, Sabri O | title = 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 | journal = European Journal of Nuclear Medicine and Molecular Imaging | volume = 48 | issue = 4 | pages = 1103–1115 | date = April 2021 | pmid = 32995944 | pmc = 8041674 | doi = 10.1007/s00259-020-05030-3 }}</ref><ref>{{cite journal | vauthors = Sahlholm K, Sijbesma JW, Maas B, Kwizera C, Marcellino D, Ramakrishnan NK, Dierckx RA, Elsinga PH, van Waarde A | title = Pridopidine selectively occupies sigma-1 rather than dopamine D2 receptors at behaviorally active doses | journal = Psychopharmacology | volume = 232 | issue = 18 | pages = 3443–3453 | date = September 2015 | pmid = 26159455 | pmc = 4537502 | doi = 10.1007/s00213-015-3997-8 }}</ref>

==Chemistry== ===Analogues=== Analogues of pridopidine include ordopidine, OSU-6162, and 3-PPP, among others.

== Potential indications == === Huntington's disease === Huntington's disease (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.<ref>{{cite journal | vauthors = McColgan P, Tabrizi SJ | title = Huntington's disease: a clinical review | journal = European Journal of Neurology | volume = 25 | issue = 1 | pages = 24–34 | date = January 2018 | pmid = 28817209 | doi = 10.1111/ene.13413 | s2cid = 24764480 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = | title = A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington's disease chromosomes. The Huntington's Disease Collaborative Research Group | journal = Cell | volume = 72 | issue = 6 | pages = 971–983 | date = March 1993 | pmid = 8458085 | doi = 10.1016/0092-8674(93)90585-e | hdl-access = free | s2cid = 802885 | hdl = 2027.42/30901 }}</ref> 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.<ref name="Huntington_Study_Group_1996">{{cite journal | vauthors = ((Huntington Study Group)) | title = Unified Huntington's Disease Rating Scale: reliability and consistency. Huntington Study Group | journal = Movement Disorders | volume = 11 | issue = 2 | pages = 136–142 | date = March 1996 | pmid = 8684382 | doi = 10.1002/mds.870110204 | s2cid = 45982731 }}</ref><ref>{{cite web | series = The Voice of the Patient: A series of reports from the FDA’s Patient-Focused Drug Development Initiative | title = Huntington's Disease | date = March 2016 | url = https://www.fda.gov/files/about%20fda/published/The-Voice-of-the-Patient--Huntington%E2%80%99s-Disease.pdf | archive-url = https://web.archive.org/web/20220316212723/https://www.fda.gov/files/about%20fda/published/The-Voice-of-the-Patient--Huntington%E2%80%99s-Disease.pdf | archive-date = 16 March 2022 | work = Center for Drug Evaluation and Research (CDER) | publisher = U.S. Food and Drug Administration (FDA) | access-date = 6 December 2021 | url-status = live }}</ref>

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.<ref name="Asla_2022">{{cite journal | vauthors = Asla MM, Nawar AA, Abdelsalam A, Elsayed E, Rizk MA, Hussein MA, Kamel WA | title = The Efficacy and Safety of Pridopidine on Treatment of Patients with Huntington's Disease: A Systematic Review and Meta-Analysis | journal = Movement Disorders Clinical Practice | volume = 9 | issue = 1 | pages = 20–30 | date = January 2022 | pmid = 35005061 | pmc = 8721839 | doi = 10.1002/mdc3.13357 }}</ref> 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.<ref name="Asla_2022" />

=== Amyotrophic lateral sclerosis === 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.<ref name="Verma_2021">{{Cite book| vauthors = Verma A |date=2021-07-25|chapter=Clinical Manifestation and Management of Amyotrophic Lateral Sclerosis|chapter-url=https://exonpublications.com/index.php/exon/article/view/386 | veditors = Araki T |title=Amyotrophic Lateral Sclerosis|publisher=Exon Publications|language=en|pages=1–14 |doi= 10.36255/exonpublications.amyotrophiclateralsclerosis.management.2021 |pmid=34473441 |isbn=978-0-645-00177-8 |s2cid=237727438}}</ref>

A phase 2 trial of the drug in ALS patients concluded in 2023 and did not reach its end points. However, one specific sub-group in the trial, patients with early and rapid onset of the disease's symptoms, did show significantly statistical improvement of their symptoms. As a result, a phase 3 trial was approved and began in early 2026. The phase 3 trial is expected to enroll 500 subjects.<ref>Stabile, Angelica, "[https://www.foxnews.com/health/breakthrough-als-study-launches-drug-aims-slow-disease-progression Breakthrough ALS study launches as drug aims to slow disease progression]", ''Fox News'', 3 April 2026</ref>

== Society and culture == === Legal status === In July 2025, the Committee for Medicinal Products for Human Use of the European Medicines Agency (EMA) recommended the refusal of a marketing authorization for Nurzigma, a medicine intended for the treatment of adults with Huntington's disease.<ref name="Nurzigma EPAR">{{cite web | title=Nurzigma EPAR | website=European Medicines Agency (EMA) | date=25 July 2025 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/nurzigma | access-date=27 July 2025}} Text was copied from this source which is copyright European Medicines Agency. Reproduction is authorized provided the source is acknowledged.</ref>

== References == {{Reflist}}

{{Other nervous system drugs}} {{Dopamine receptor modulators}} {{Sigma receptor modulators}} {{Portal bar | Medicine}} {{Authority control}}

Category:Benzosulfones Category:D2 antagonists Category:Huntington's disease Category:4-Phenylpiperidines Category:Sigma agonists Category:Propyl compounds Category:Mesyl compounds