Pramipexole

Pramipexole is used in the treatment of Parkinson's disease and restless legs syndrome. Safety in pregnancy and breastfeeding is unknown.{{cite web |title=Pramipexole Pregnancy and Breastfeeding Warnings |url=https://www.drugs.com/pregnancy/pramipexole.html |url-status=live |archive-url=https://web.archive.org/web/20190322133525/https://www.drugs.com/pregnancy/pramipexole.html |archive-date=22 March 2019 |access-date=3 March 2019 |website=Drugs.com}}

A 2008 meta-analysis found that pramipexole was more effective than ropinirole in the treatment of restless legs syndrome.{{cite journal | vauthors = Quilici S, Abrams KR, Nicolas A, Martin M, Petit C, Lleu PL, Finnern HW | title = Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome | journal = Sleep Med | volume = 9 | issue = 7 | pages = 715–26 | date = October 2008 | pmid = 18226947 | doi = 10.1016/j.sleep.2007.11.020 | url = }}

It is occasionally prescribed off-label for depression. Its effectiveness as an antidepressant may be a product of its strong partial agonistic activity on and preferential occupation of dopamine D₃ receptors at low doses (see table below); as well, the drug has been shown to desensitize the inhibitory D₂ autoreceptors but not the postsynaptic D₂ receptors, leading to an increase in dopamine and serotonin levels in the prefrontal cortex.{{cite journal | vauthors = Chernoloz O, El Mansari M, Blier P | title = Long-term administration of the dopamine D3/2 receptor agonist pramipexole increases dopamine and serotonin neurotransmission in the male rat forebrain | journal = Journal of Psychiatry & Neuroscience | volume = 37 | issue = 2 | pages = 113–121 | date = February 2012 | pmid = 22023785 | pmc = 3297071 | doi = 10.1503/jpn.110038 }} Chronic administration of pramipexole may also result in desensitization of D₃ autoreceptors, leading to reduced dopamine transporter function.{{cite journal | vauthors = Castro-Hernández J, Afonso-Oramas D, Cruz-Muros I, Salas-Hernández J, Barroso-Chinea P, Moratalla R, Millan MJ, González-Hernández T | title = Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake | journal = Neurobiology of Disease | volume = 74 | pages = 325–335 | date = February 2015 | pmid = 25511804 | doi = 10.1016/j.nbd.2014.12.007 }} Trials have shown mixed results for depression.{{cite journal | vauthors = Fawcett J, Rush AJ, Vukelich J, Diaz SH, Dunklee L, Romo P, Yarns BC, Escalona R | title = Clinical Experience With High-Dosage Pramipexole in Patients With Treatment-Resistant Depressive Episodes in Unipolar and Bipolar Depression | journal = The American Journal of Psychiatry | volume = 173 | issue = 2 | pages = 107–111 | date = February 2016 | pmid = 26844792 | doi = 10.1176/appi.ajp.2015.15060788 | doi-access = free }}

Pramipexole has also been used as a treatment for REM sleep behaviour disorder, but it is not licensed for use in this disorder. Observational studies suggest it may reduce the frequency and intensity of REM sleep behavior disorder symptoms, but randomized controlled trials have not been performed, so the evidence for its role in this disorder is weak.{{cite journal | vauthors = Tan SM, Wan YM | title = Pramipexole in the treatment of REM sleep behaviour disorder: A critical review | journal = Psychiatry Res | volume = 243 | pages = 365–372 | date = 30 September 2016 | pmid = 27449005 | doi = 10.1016/j.psychres.2016.06.055 }}

Common side effects of pramipexole include:{{cite web |url= https://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203739.html |title= MedlinePlus Drug Information: Pramipexole (Systemic) |access-date= 27 September 2006 |publisher= United States National Library of Medicine |archive-url = https://web.archive.org/web/20060926023858/http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/203739.html |archive-date = 26 September 2006}}{{cite web | title=Mirapex- pramipexole dihydrochloride tablet | website=DailyMed | date=1 March 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=688fa4d7-de12-4930-8bc5-0169297c1da6 | access-date=17 October 2020 | archive-date=18 October 2020 | archive-url=https://web.archive.org/web/20201018092447/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=688fa4d7-de12-4930-8bc5-0169297c1da6 | url-status=live }}{{cite web | title=Mirapex ER- pramipexole dihydrochloride tablet, extended release | website=DailyMed | date=5 February 2020 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2902ed1-cfeb-4815-adc3-129c577917a1 | access-date=17 October 2020 | archive-date=21 October 2020 | archive-url=https://web.archive.org/web/20201021152917/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=e2902ed1-cfeb-4815-adc3-129c577917a1 | url-status=live }}

• Headache
• Peripheral edema{{cite journal | vauthors = Tan EK, Ondo W | title = Clinical characteristics of pramipexole-induced peripheral edema | journal = Archives of Neurology | volume = 57 | issue = 5 | pages = 729–732 | date = May 2000 | pmid = 10815140 | doi = 10.1001/archneur.57.5.729 | doi-access = free }}
• Hyperalgesia (body aches and pains)
• Nausea and vomiting
• Sedation and somnolence
• Decreased appetite and subsequent weight loss
• Orthostatic hypotension (resulting in dizziness, lightheadedness, and possibly fainting, especially when standing up)
• Insomnia
• Hallucinations (seeing, hearing, smelling, tasting or feeling things that are not there), amnesia and confusion
• Twitching, twisting, or other unusual body movements
• Unusual tiredness or weakness
• Pramipexole (and related D₃-preferring dopamine agonist medications such as ropinirole) can induce "impulsive-compulsive spectrum disorders"{{cite journal |vauthors=Napier TC, Kirby A, Persons AL |date=August 2020 |title=The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease |journal=Progress in Neuro-Psychopharmacology & Biological Psychiatry |volume=102 |page=109942 |doi=10.1016/j.pnpbp.2020.109942 |pmid=32272129 |quote=... features of ICSDs [impulsive-compulsive spectrum disorders] during D2/D3R treatment are consistent with the pharmacological profile of the drugs, the known role of D2/D3R in these behaviors, and the neuroanatomical substrates of D2/D3R-expressing brain systems of ICSDs as shown by modern human imaging studies. While we pose that D2/D3R agonist treatment is sufficient to mediate ICSDs, there likely are many factors that overlay this profile, e.g., genetic vulnerabilities, brain disease state, and maladaptations to the chronic therapy.}} such as compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviors.{{cite journal |vauthors=Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE |date=April 2009 |title=Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease |journal=Mayo Clinic Proceedings |volume=84 |issue=4 |pages=310–316 |doi=10.4065/84.4.310 |pmc=2665974 |pmid=19339647}}{{cite journal |vauthors=Moore TJ, Glenmullen J, Mattison DR |date=December 2014 |title=Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs |journal=JAMA Internal Medicine |volume=174 |issue=12 |pages=1930–1933 |doi=10.1001/jamainternmed.2014.5262 |pmid=25329919 |doi-access=free}}{{cite journal |vauthors=Wolters EC, van der Werf YD, van den Heuvel OA |date=September 2008 |title=Parkinson's disease-related disorders in the impulsive-compulsive spectrum |journal=Journal of Neurology |volume=255 |issue=Suppl 5 |pages=48–56 |doi=10.1007/s00415-008-5010-5 |pmid=18787882 }} There have also been reported detrimental side effects related to impulse-control disorders resulting from off-label use of Pramipexole or other dopamine agonists in treating clinical depression.{{cite web |title=The Degradation Drug |url=https://theamericanscholar.org/the-degradation-drug/ |url-status=live |archive-url=https://web.archive.org/web/20220915020333/https://theamericanscholar.org/the-degradation-drug/ |archive-date=15 September 2022 |access-date=15 September 2022 |website=The American Scholar |vauthors=Elliott C}} The incidence and severity of impulse-control disorders for those taking the drug for depression are not fully understood because the drug has not been approved for the treatment of depression and the first major studies of its efficacy in treating anhedonic depression were conducted in 2022. There have been anecdotal reports of abrupt and severe personality changes related to impulsivity and loss of self-control in a minority of patients regardless of the condition being treated, although the incidence of these side effects is not yet fully known.
• Augmentation:{{efn|The term "augmentation" has different meanings depending on the context. In the context of the pharmacological management of psychiatric disorders, for example, it means enhancing treatment effects by adding a second drug (or other treatment intervention). In the present context, augmentation has the meaning given above (in the body of the article).}} Especially when used to treat restless legs syndrome, long-term pramipexole treatment may exhibit drug augmentation, which is "an iatrogenic worsening of [restless legs syndrome] symptoms following treatment with dopaminergic agents"{{cite journal | vauthors = Winkelmann J, Allen RP, Högl B, Inoue Y, Oertel W, Salminen AV, Winkelman JW, Trenkwalder C, Sampaio C | title = Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)^§ | journal = Movement Disorders | volume = 33 | issue = 7 | pages = 1077–1091 | date = July 2018 | pmid = 29756335 | doi = 10.1002/mds.27260 | quote = ... the specific goals of the current review were to … separately identify the [restless legs syndrome]-specific side effect, which is augmentation. }} and may include an earlier onset of symptoms during the day or a generalized increase in symptoms.{{Cite web|title=Pramipexole Monograph for Professionals|url=https://www.drugs.com/monograph/pramipexole.html|access-date=11 December 2020|website=Drugs.com|language=en|quote=Augmentation of symptoms of restless legs syndrome (e.g., earlier onset of symptoms in the evening or afternoon, increase in symptoms, spread of symptoms to involve other extremities) reported; incidence increased with increasing duration of pramipexole treatment.|archive-date=25 November 2021|archive-url=https://web.archive.org/web/20211125234216/https://www.drugs.com/monograph/pramipexole.html|url-status=live}}{{cite journal | vauthors = Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, Zee PC, Gronseth GS, Gloss D, Zesiewicz T | title = Practice guideline summary: Treatment of restless legs syndrome in adults: Report of the Guideline Development, Dissemination, and Implementation Subcommittee of the American Academy of Neurology | journal = Neurology | volume = 87 | issue = 24 | pages = 2585–2593 | date = December 2016 | pmid = 27856776 | pmc = 5206998 | doi = 10.1212/WNL.0000000000003388 }}{{cite journal | vauthors = Salminen AV, Winkelmann J | title = Restless Legs Syndrome and Other Movement Disorders of Sleep-Treatment Update | journal = Current Treatment Options in Neurology | volume = 20 | issue = 12 | page = 55 | date = November 2018 | pmid = 30411165 | doi = 10.1007/s11940-018-0540-3 | quote = … augmentation of the [restless legs syndrome] symptoms is a major limitation of oral dopaminergic therapy.}}

The activity profile of Pramipexole at various sites has been characterized as follows:

File:Pramipexole.er.4.5mg.jpg

While Pramipexole is used clinically (see below), its D₃-preferring receptor binding profile has made it a popular tool compound for preclinical research. For example, pramipexole has been used (in combination with D₂- and or D₃-preferring antagonists) to discover the role of D₃ receptor function in rodent models and tasks for neuropsychiatric disorders.{{cite journal | vauthors = Weber M, Chang WL, Breier M, Ko D, Swerdlow NR | title = Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation | journal = Behavioural Pharmacology | volume = 19 | issue = 8 | pages = 786–795 | date = December 2008 | pmid = 19020413 | pmc = 3255557 | doi = 10.1097/FBP.0b013e32831c3b2b }} Of note, it appears that pramipexole, in addition to having effects on dopamine D₃ receptors, may also affect mitochondrial function via a mechanism that remains less understood. A pharmacological approach to separate dopaminergic from non-dopaminergic (e.g. mitochondrial) effects of pramipexole has been to study the effects of the R-stereoisomer of pramipexole (which has much lower affinity to the dopamine receptors when compared to the S-isomer) side by side with the effects of the S-isomer.{{cite journal | vauthors = Chang WL, Weber M, Breier MR, Saint Marie RL, Hines SR, Swerdlow NR | title = Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats | journal = Brain Research | volume = 1437 | pages = 69–76 | date = February 2012 | pmid = 22227455 | pmc = 3268831 | doi = 10.1016/j.brainres.2011.12.007 }} This property can be characterised using dopaminergic activity equivalent (a relative measure comparing doses of different doses of stereoisomers in mg).{{Cite patent|number=EP2508181A1|title=Compositions and Methods Of Using (R)-Pramipexole|gdate=2012-10-10|invent1=Bozik|invent2=Jr|invent3=Gribkoff|inventor1-first=Michael E.|inventor2-first=Thomas Petzinger|inventor3-first=Valentin|url=https://patents.google.com/patent/EP2508181A1/en?oq=EP+2508181+A1}}

File:Pramipexole02point5mgAUCinfinity.pngParkinson's disease is a neurodegenerative disease affecting the substantia nigra, a component of the basal ganglia. The substantia nigra has a high quantity of dopaminergic neurons, which are nerve cells that release the neurotransmitter known as dopamine. When dopamine is released, it may activate dopamine receptors in the striatum, which is another component of the basal ganglia. When neurons of the substantia nigra deteriorate in Parkinson's disease, the striatum no longer properly receives dopamine signals. As a result, the basal ganglia can no longer regulate body movement effectively and motor function becomes impaired. By acting as an agonist for the D₂, D₃, and D₄ dopamine receptors, pramipexole may directly stimulate the underfunctioning dopamine receptors in the striatum, thereby restoring the dopamine signals needed for proper functioning of the basal ganglia.

Pramipexole can increase growth hormone indirectly through its inhibition of somatostatin.{{cite journal | vauthors = Samuels ER, Hou RH, Langley RW, Szabadi E, Bradshaw CM | title = Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers | journal = British Journal of Clinical Pharmacology | volume = 64 | issue = 5 | pages = 591–602 | date = November 2007 | pmid = 17578485 | pmc = 2203276 | doi = 10.1111/j.1365-2125.2007.02938.x }} Pramipexole has also been shown to be protective against dopaminergic-related methamphetamine neurotoxicity.{{cite journal | vauthors = Hall ED, Andrus PK, Oostveen JA, Althaus JS, VonVoigtlander PF | title = Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons | journal = Brain Research | volume = 742 | issue = 1–2 | pages = 80–88 | date = December 1996 | pmid = 9117424 | doi = 10.1016/S0006-8993(96)00968-7 }}{{cite web | title = Pramipexole | work = Drug Bank | url = https://go.drugbank.com/drugs/DB00413}}

File:MIRAPEX-ERvsIR.jpg

Immediate-release pramipexole displays a T_max of approximately 2 hours and 3 hours if taken with a high-fat meal. Extended-release pramipexole displays a T_max of ~6 hours and ~8 hours if taken with food. The AUC of Pramipexole remains unaltered regardless of food presence. Steady-state is achieved within 3 days and 5 days for the IR and ER formulation respectively. Pramipexole is eliminated via the renal organic cation transporter as an unchanged drug showing no signs of any metabolism. Pramipexole has been shown to inhibit CYP2D6 with a K_i of 30μM which is significantly higher than the maximum approved dosage of 4.5mg/day thus any enzyme-mediated drug interactions are not clinically relevant. It comes in strengths of 0.125mg, 0.25mg, 0.5mg, 1mg, and 1.5mg instant release; the extended-release comes in 0.375mg, 0.75mg, 1.5mg, 2.25mg, 3mg, 3.75mg, and 4.5mg. The instant release is meant to be dosed three times daily for Parkinson's and once two hours before bedtime for restless leg syndrome. The extended-release is not approved for restless leg syndrome. It is not metabolized, with >90% of the dose excreted unchanged via SCL22A2/OCT2. Therefore, inhibitors of the renal organic cation transporter system (e.g., cimetidine ) will increase the area under the curve$\backslash infty$ by 50% and increase the t_1/2 by 40%.https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020667s025lbl.pdfhttps://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022421s023lbl.pdf

4-Acetamidocyclohexanone (1) is reacted with bromine, yielding 2-bromo-4-acetamidocyclohexanone (2). Then, 2 reacts with thiourea, giving compound 3. Through reaction with HBr, amide is converted into a primary amine (compound 4), which then reacts with diethyl mesoxalate and tetrahydroborane, yielding pramipexole (5).

File:Pramipexole synthesis.svg

Brand names include Mirapex, Mirapex ER, Mirapexin, Sifrol, Pexola,{{Cite web |title=Sifrol |url=https://www.boehringer-ingelheim.com/human-health/products/sifrol |access-date=2025-02-27 |website=www.boehringer-ingelheim.com}} Pipexus,{{Cite web |title=Pipexus 0.52 mg Prolonged-release Tablets - Summary of Product Characteristics (SmPC) - (emc) |url=https://www.medicines.org.uk/emc/product/10990/smpc#gref |access-date=2025-02-27 |website=www.medicines.org.uk}} Glepark,{{Cite web |title=Glepark Tabletten |url=https://www.glenmark.de/praeparate/glepark-tabletten/ |access-date=2025-02-27 |website=www.glenmark.de}} Oprymea,{{Cite web |title=Oprymea - 1,05 mg, tabletki o przedłużonym uwalnianiu |url=https://www.krka-polska.pl/produkty/nasze-produkty/leki-na-recepte/oprymea-r-tabl-o-przedl-uwaln-1-05-mg-x-30-szt/ |access-date=2025-02-27 |website=Krka |language=pl}} Astepen, Calmolan, Erimexol, Ezaprev, Frodix, Galipeks, Labrixile, Mariprax, Medopexol, Mepimer, Minergi, Miparkan, Miraper, Miviren, Nulipar, Pacto, Panarak, Parim, Parixol, Parkipex, Parkyn, Parmital, Parpex, Pexa XR, Peximyr, Pexopar, Pisa, Portiv, Pradose, Pramigen, Pramipexin, Pramirol, Pramithon, Pranow, Prapex, Quera LP, Rampiex, Ramixole, Rapexole, Ritmorest, Axalanz, Biopsol, Derinik, Elderpat, Intaxel, Mirapapkin, Mirapezol, Movial, Muvend, Nervius, Neurosomat, Newmirex, Noxopran, Nulipar, Oxpola, Parmital, Periamid, Pralexan, Pramexol, Pramifer, Pramiola, Pramip, Pramitrem, Primizol, Ramipex, Rapexole, Simipex, Simpral, Stabil, Treminel, Trimexol, X-Tremble.{{Cite web |title=Pramipexole (International database) |url=https://www.drugs.com/international/pramipexole.html |access-date=2025-02-27 |website=Drugs.com |language=en}}

Parkinson's disease, apart from motor symptoms, is associated with chronic pain,{{cite journal | vauthors = Mylius V, Ciampi de Andrade D, Cury RG, Teepker M, Ehrt U, Eggert KM, Beer S, Kesselring J, Stamelou M, Oertel WH, Möller JC, Lefaucheur JP | title = Pain in Parkinson's Disease: Current Concepts and a New Diagnostic Algorithm | journal = Movement Disorders Clinical Practice | volume = 2 | issue = 4 | pages = 357–364 | date = December 2015 | pmid = 30363602 | pmc = 6178768 | doi = 10.1002/mdc3.12217 }} which is mediated through three different mechanisms: nociception, neuropathy and nociplasty.{{cite journal | vauthors = Mylius V, Perez Lloret S, Cury RG, Teixeira MJ, Barbosa VR, Barbosa ER, Moreira LI, Listik C, Fernandes AM, de Lacerda Veiga D, Barbour J, Hollenstein N, Oechsner M, Walch J, Brugger F, Hägele-Link S, Beer S, Rizos A, Chaudhuri KR, Bouhassira D, Lefaucheur JP, Timmermann L, Gonzenbach R, Kägi G, Möller JC, Ciampi de Andrade D | title = The Parkinson disease pain classification system: results from an international mechanism-based classification approach | journal = Pain | volume = 162 | issue = 4 | pages = 1201–1210 | date = April 2021 | pmid = 33044395 | pmc = 7977616 | doi = 10.1097/j.pain.0000000000002107 }} In animal models, it was shown that pramipexole alleviates allodynia and hyperalgesia{{cite journal | vauthors = Godínez-Chaparro B, Rodríguez-Ramos MC, Martínez-Lorenzana MG, González-Morales E, Pérez-Ruíz KP, Espinosa de Los Monteros-Zuñiga A, Mendoza-Pérez F, Condes-Lara M | title = Pramipexole decreases allodynia and hyperalgesia via NF-κB in astrocytes in rats with Parkinson's disease | journal = Pharmacology, Biochemistry, and Behavior | volume = 247 | pages = 173945 | date = February 2025 | pmid = 39675389 | doi = 10.1016/j.pbb.2024.173945 | doi-access = free }} caused by excessive glial cell (astrocytes, microglia) activation in the spinal cord, which is the causative effect of Parkinson's disease-relatet nociceptive pain.{{cite journal | vauthors = Chen Y, Li Y, Li C, Zhu D, Cheng O, Cui J | title = Dexmedetomidine alleviates pain in MPTP-treated mice by activating the AMPK/mTOR/NF-κB pathways in astrocytes | journal = Neuroscience Letters | volume = 791 | pages = 136933 | date = November 2022 | pmid = 36283628 | doi = 10.1016/j.neulet.2022.136933 }} Pramipexole appears to exert this effect through its anti-inflammatory effect by inhibiting the release of several pro-inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-8, IL-12 and IL-18).{{cite journal | vauthors = Rocha NP, Assis F, Scalzo PL, Vieira ÉL, Barbosa IG, de Souza MS, Christo PP, Reis HJ, Teixeira AL | title = Reduced Activated T Lymphocytes (CD4+CD25+) and Plasma Levels of Cytokines in Parkinson's Disease | journal = Molecular Neurobiology | volume = 55 | issue = 2 | pages = 1488–1497 | date = February 2018 | pmid = 28176275 | doi = 10.1007/s12035-017-0404-y }}{{cite journal | vauthors = Lieberknecht V, Junqueira SC, Cunha MP, Barbosa TA, de Souza LF, Coelho IS, Santos AR, Rodrigues AL, Dafré AL, Dutra RC | title = Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice | journal = Molecular Neurobiology | volume = 54 | issue = 2 | pages = 1033–1045 | date = March 2017 | pmid = 26801190 | doi = 10.1007/s12035-016-9717-5 }}{{cite journal | vauthors = Sanchez JE, Noor S, Sun MS, Zimmerly J, Pasmay A, Sanchez JJ, Vanderwall AG, Haynes MK, Sklar LA, Escalona PR, Milligan ED | title = The FDA-approved compound, pramipexole and the clinical-stage investigational drug, dexpramipexole, reverse chronic allodynia from sciatic nerve damage in mice, and alter IL-1β and IL-10 expression from immune cell culture | journal = Neuroscience Letters | volume = 814 | pages = 137419 | date = September 2023 | pmid = 37558176 | pmc = 10552878 | doi = 10.1016/j.neulet.2023.137419 }} and NF-κB.{{cite journal | vauthors = Santamaria-Anzures J, Pérez-Ramos J, Mendoza-Pérez F, Godínez-Chaparro B | title = Pramipexole inhibits formalin-induce acute and long-lasting mechanical hypersensitivity via NF-kB pathway in rats | journal = Drug Development Research | volume = 84 | issue = 2 | pages = 253–261 | date = April 2023 | pmid = 36651647 | doi = 10.1002/ddr.22029 }}

Pramipexole in combination with levodopa was shown to alleviate neurological repercussions, improve neuron morphology and their survival after cerebral ischemia-related reperfusion injury through ferroptosis inhibition (via Nrf2/GPX4/SLC7A11 pathway){{cite journal | vauthors = Kang X, Wang W, Zuo Y, Wang Y, Zhang L, Liu L | title = Dopamine receptor agonist pramipexole exerts neuroprotection on global cerebral ischemia/reperfusion injury by inhibiting ferroptosis | language = English | journal = Journal of Stroke and Cerebrovascular Diseases | volume = 34 | issue = 1 | pages = 108101 | date = January 2025 | pmid = 39490461 | doi = 10.1016/j.jstrokecerebrovasdis.2024.108101 | doi-access = free }} or by mitochondrial membrane potential stabilization.{{cite journal | vauthors = Kang X, Liu L, Wang W, Wang Y | title = Effects of different doses of dopamine receptor agonist pramipexole on neurobehaviors and changes of mitochondrial membrane potentials in rats with global cerebral ischemia-reperfusion injury | language = English | journal = Journal of Stroke and Cerebrovascular Diseases | volume = 32 | issue = 7 | pages = 107142 | date = July 2023 | pmid = 37105127 | doi = 10.1016/j.jstrokecerebrovasdis.2023.107142 }}

After traumatic brain injury, neurons can undergo necroptosis via necrosome formation and RIPK1 pathway.{{cite journal | vauthors = Stanger BZ, Leder P, Lee TH, Kim E, Seed B | title = RIP: a novel protein containing a death domain that interacts with Fas/APO-1 (CD95) in yeast and causes cell death | journal = Cell | volume = 81 | issue = 4 | pages = 513–523 | date = May 1995 | pmid = 7538908 | doi = 10.1016/0092-8674(95)90072-1 }}{{cite journal | vauthors = Wang L, Du F, Wang X | title = TNF-alpha induces two distinct caspase-8 activation pathways | language = English | journal = Cell | volume = 133 | issue = 4 | pages = 693–703 | date = May 2008 | pmid = 18485876 | doi = 10.1016/j.cell.2008.03.036 }}{{cite journal | vauthors = Galluzzi L, Kroemer G | title = Necroptosis: a specialized pathway of programmed necrosis | language = English | journal = Cell | volume = 135 | issue = 7 | pages = 1161–1163 | date = December 2008 | pmid = 19109884 | doi = 10.1016/j.cell.2008.12.004 }} Pramipexole was shown to act as a neuroprotective agent by inducing hypothermia.{{cite journal | vauthors = Liu C, Sun X, Cai Y, Li D, Li B, Gao R, Zhang L, Chen G | title = Pramipexole alleviates traumatic brain injury in rats through inhibiting necroptosis | journal = Neuroscience Letters | volume = 791 | pages = 136911 | date = November 2022 | pmid = 36243204 | doi = 10.1016/j.neulet.2022.136911 }}

Pramipexole has been evaluated for the treatment of sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor antidepressants.{{cite journal | vauthors = DeBattista C, Solvason HB, Breen JA, Schatzberg AF | title = Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression | journal = Journal of Clinical Psychopharmacology | volume = 20 | issue = 2 | pages = 274–275 | date = April 2000 | pmid = 10770475 | doi = 10.1097/00004714-200004000-00029 }} It has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder.{{cite journal | vauthors = Zarate CA, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, Charney DS, Manji HK | title = Pramipexole for bipolar II depression: a placebo-controlled proof of concept study | journal = Biological Psychiatry | volume = 56 | issue = 1 | pages = 54–60 | date = July 2004 | pmid = 15219473 | doi = 10.1016/j.biopsych.2004.03.013 }}{{cite journal | vauthors = Goldberg JF, Burdick KE, Endick CJ | title = Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression | journal = The American Journal of Psychiatry | volume = 161 | issue = 3 | pages = 564–566 | date = March 2004 | pmid = 14992985 | doi = 10.1176/appi.ajp.161.3.564 }}{{cite journal | vauthors = Goodwin GM, Martinez-Aran A, Glahn DC, Vieta E | title = Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? An ECNP expert meeting report | journal = European Neuropsychopharmacology | volume = 18 | issue = 11 | pages = 787–793 | date = November 2008 | pmid = 18725178 | doi = 10.1016/j.euroneuro.2008.07.005 }}{{Cite journal | vauthors = McAllister-Williams H, Chadwick T, Courtney P, Moore A, Fouweather T, Geddes J, Goudie N, Morriss R, Simon J, Smith D, Stokes P |date=2023-01-01 |title=A randomised double-blind, placebo-controlled trial of pramipexole for patients with treatment resistant bipolar depression (the Pramipexole Trial for Bipolar Depression) |journal=Neuroscience Applied |series=Abstracts of the 36th ECNP Congress 2023 |volume=2 |page=102938 |doi=10.1016/j.nsa.2023.102938 |issn=2772-4085|doi-access=free }} It is also being investigated for the treatment of clinical depression,{{cite journal | vauthors = Lattanzi L, Dell'Osso L, Cassano P, Pini S, Rucci P, Houck PR, Gemignani A, Battistini G, Bassi A, Abelli M, Cassano GB | title = Pramipexole in treatment-resistant depression: a 16-week naturalistic study | journal = Bipolar Disorders | volume = 4 | issue = 5 | pages = 307–314 | date = October 2002 | pmid = 12479663 | doi = 10.1034/j.1399-5618.2002.01171.x }}{{cite journal | vauthors = Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, Cassano GB | title = Pramipexole in treatment-resistant depression: an extended follow-up | journal = Depression and Anxiety | volume = 20 | issue = 3 | pages = 131–138 | year = 2004 | pmid = 15549689 | doi = 10.1002/da.20038 | doi-access = free }} including neuroinflammatory subtypes via NLRP3 inflammasome pathway.{{cite journal | vauthors = Li P, Wang T, Guo H, Liu Y, Zhao H, Ren T, Tang Y, Wang Y, Zou M | title = Pramipexole improves depression-like behavior in diabetes mellitus with depression rats by inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing impaired neuroplasticity | journal = Journal of Affective Disorders | volume = 356 | pages = 586–596 | date = July 2024 | pmid = 38657764 | doi = 10.1016/j.jad.2024.04.073 }}

Pramipexole is under clinical trials for the treatment of fibromyalgia,{{cite journal | vauthors = Holman AJ, Myers RR | title = A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications | journal = Arthritis and Rheumatism | volume = 52 | issue = 8 | pages = 2495–2505 | date = August 2005 | pmid = 16052595 | doi = 10.1002/art.21191 | doi-access = free }} essential tremor,{{cite journal | vauthors = Herceg M, Nagy F, Pál E, Janszky J, Késmárky I, Komoly S, Kovács N | title = Pramipexole may be an effective treatment option in essential tremor | journal = Clinical Neuropharmacology | volume = 35 | issue = 2 | pages = 73–76 | date = March 2012 | pmid = 22318193 | doi = 10.1097/WNF.0b013e31824687bf }}{{cite journal | vauthors = Kosmowska B, Wardas J, Głowacka U, Ananthan S, Ossowska K | title = Pramipexole at a Low Dose Induces Beneficial Effect in the Harmaline-induced Model of Essential Tremor in Rats | journal = CNS Neuroscience & Therapeutics | volume = 22 | issue = 1 | pages = 53–62 | date = January 2016 | pmid = 26459182 | pmc = 6492867 | doi = 10.1111/cns.12467 }} primary orthostatic tremor ('shaky leg syndrome'),{{cite journal | vauthors = Finkel MF | title = Pramipexole is a possible effective treatment for primary orthostatic tremor (shaky leg syndrome) | journal = Archives of Neurology | volume = 57 | issue = 10 | pages = 1519–1520 | date = October 2000 | pmid = 11030807 | doi = 10.1001/archneur.57.10.1519 }} persistent genital arousal disorder.{{cite journal | vauthors = Lynn BK, Grabenhorst C, Komisaruk BR, Goldstein I, Pfaus J | title = The Use of Pramipexole to Treat Persistent Genital Arousal Disorder: A Case Report | journal = Sexual Medicine | volume = 9 | issue = 4 | pages = 100372 | date = August 2021 | pmid = 34126431 | pmc = 8360918 | doi = 10.1016/j.esxm.2021.100372 }}

Derivatives of Pramipexole include CJ-998, CJ-1037, CJ-1638, CJ-1639,{{cite journal | vauthors = Chen J, Collins GT, Levant B, Woods J, Deschamps JR, Wang S | title = CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist | journal = ACS Medicinal Chemistry Letters | volume = 2 | issue = 8 | pages = 620–625 | date = August 2011 | pmid = 22125662 | doi = 10.1021/ml200100t | pmc = 3224040 }} D-264, D-440,{{cite journal | vauthors = Santra S, Xu L, Shah M, Johnson M, Dutta A | title = D-512 and D-440 as novel multifunctional dopamine agonists: characterization of neuroprotection properties and evaluation of in vivo efficacy in a Parkinson's disease animal model | journal = ACS Chemical Neuroscience | volume = 4 | issue = 10 | pages = 1382–1392 | date = October 2013 | pmid = 23906010 | doi = 10.1021/cn400106n | pmc = 3798991 }} and D-512.

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