Pramipexole was approved for medical use in the United States in 1997[8] and was first manufactured byPharmacia andUpjohn.[9] It is available as ageneric medication.[10] In 2023, it was the 201st most commonly prescribed medication in the United States, with more than 2million prescriptions.[11][12]
Pramipexole bound to the Dopamine D3 receptor PDB - 7CMU
A 2008meta-analysis found that pramipexole was more effective thanropinirole in the treatment of restless legs syndrome.[13]
It is occasionally prescribedoff-label fordepression. 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 theprefrontal cortex.[14] Chronic administration of pramipexole may also result in desensitization of D3 autoreceptors, leading to reduced dopamine transporter function.[15] Trials have shown mixed results for depression.[16]
Pramipexole has also been used as a treatment forREM 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.[17]
Pramipexole (and related D3-preferring dopamine agonist medications such asropinirole) can induce "impulsive-compulsive spectrum disorders"[20] such ascompulsive gambling,punding,hypersexuality, andovereating, even in people without any prior history of these behaviors.[21][22][23] There have also been reported detrimental side effects related to impulse-control disorders resulting fromoff-label use of Pramipexole or other dopamine agonists in treating clinical depression.[24] 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.[24]
Augmentation:[a] Especially when used to treatrestless 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"[25] and may include an earlier onset of symptoms during the day or a generalized increase in symptoms.[26][27][28]
Full agonist (Gi/o); Partial agonist (β-arrestin) [functionally G-protein biased]
Notes: Pramipexole also possesses lower affinity (500–10,000 nM) for the5-HT1A,5-HT1B,5-HT1D, andα2-adrenergic receptors.[29][35] It has negligible affinity (>10,000 nM) for theD1,D5,5-HT2,α1-adrenergic,β-adrenergic,H1, andmACh receptors.[29][35] All sites were assayed using human materials.[29][30] Pramipexole is asuperagonist at the presynaptic D2S receptor, S referring to a shorter amino acid sequence commonly found presynaptically, which desensitizes over time unlike postsynaptic D2L (long) receptors.
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.[36] 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 theR-stereoisomer of pramipexole (which has much lower affinity to the dopamine receptors when compared to theS-isomer) side by side with the effects of theS-isomer.[37] This property can be characterised usingdopaminergic activity equivalent (a relative measure comparing doses of different doses of stereoisomers in mg).[38]
Plasma Concentration of 0.25mg PO after a single dose.
Parkinson's disease is aneurodegenerative disease affecting thesubstantia nigra, a component of thebasal ganglia. The substantia nigra has a high quantity ofdopaminergicneurons, which arenervecells thatrelease theneurotransmitter known asdopamine. When dopamine is released, it may activatedopamine receptors in thestriatum, 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 thestriatum, thereby restoring the dopamine signals needed for proper functioning of the basal ganglia.
Plasma concentration of Mirapex and Mirapex ER at steady-state
Immediate-release pramipexole displays a Tmax of approximately 2 hours and 3 hours if taken with a high-fat meal. Extended-release pramipexole displays a Tmax 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 Ki 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 viaSCL22A2/OCT2. Therefore, inhibitors of the renal organic cation transporter system (e.g.,cimetidine ) will increase thearea under the curve by 50% and increase thet1/2 by 40%.[42][43]
4-Acetamidocyclohexanone (1) is reacted with bromine, yielding 2-bromo-4-acetamidocyclohexanone (2). Then,2 reacts with thiourea, giving compound3. Through reaction with HBr, amide is converted into a primary amine (compound4), which then reacts with diethyl mesoxalate and tetrahydroborane, yielding pramipexole (5).
^The term "augmentation" has different meanings depending on the context. In the context of thepharmacological 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).
^Quilici S, Abrams KR, Nicolas A, Martin M, Petit C, Lleu PL, et al. (October 2008). "Meta-analysis of the efficacy and tolerability of pramipexole versus ropinirole in the treatment of restless legs syndrome".Sleep Med.9 (7):715–26.doi:10.1016/j.sleep.2007.11.020.PMID18226947.
^Tan SM, Wan YM (30 September 2016). "Pramipexole in the treatment of REM sleep behaviour disorder: A critical review".Psychiatry Res.243:365–372.doi:10.1016/j.psychres.2016.06.055.PMID27449005.
^Napier TC, Kirby A, Persons AL (August 2020). "The role of dopamine pharmacotherapy and addiction-like behaviors in Parkinson's disease".Progress in Neuro-Psychopharmacology & Biological Psychiatry.102 109942.doi:10.1016/j.pnpbp.2020.109942.PMID32272129.... 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.
^Wolters EC, van der Werf YD, van den Heuvel OA (September 2008). "Parkinson's disease-related disorders in the impulsive-compulsive spectrum".Journal of Neurology.255 (Suppl 5):48–56.doi:10.1007/s00415-008-5010-5.PMID18787882.
^abElliott C."The Degradation Drug".The American Scholar.Archived from the original on 15 September 2022. Retrieved15 September 2022.
^Winkelmann J, Allen RP, Högl B, Inoue Y, Oertel W, Salminen AV, et al. (July 2018). "Treatment of restless legs syndrome: Evidence-based review and implications for clinical practice (Revised 2017)§".Movement Disorders.33 (7):1077–1091.doi:10.1002/mds.27260.PMID29756335.... the specific goals of the current review were to … separately identify the [restless legs syndrome]-specific side effect, which is augmentation.
^"Pramipexole Monograph for Professionals".Drugs.com.Archived from the original on 25 November 2021. Retrieved11 December 2020.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.
^Salminen AV, Winkelmann J (November 2018). "Restless Legs Syndrome and Other Movement Disorders of Sleep-Treatment Update".Current Treatment Options in Neurology.20 (12): 55.doi:10.1007/s11940-018-0540-3.PMID30411165.… augmentation of the [restless legs syndrome] symptoms is a major limitation of oral dopaminergic therapy.
^abcdKvernmo T, Härtter S, Burger E (August 2006). "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists".Clinical Therapeutics.28 (8):1065–1078.doi:10.1016/j.clinthera.2006.08.004.PMID16982285.
^abNewman-Tancredi A, Cussac D, Audinot V, Nicolas JP, De Ceuninck F, Boutin JA, et al. (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. II. Agonist and antagonist properties at subtypes of dopamine D(2)-like receptor and alpha(1)/alpha(2)-adrenoceptor".The Journal of Pharmacology and Experimental Therapeutics.303 (2):805–814.doi:10.1124/jpet.102.039875.PMID12388667.
^Mierau J, Schneider FJ, Ensinger HA, Chio CL, Lajiness ME, Huff RM (June 1995). "Pramipexole binding and activation of cloned and expressed dopamine D2, D3 and D4 receptors".European Journal of Pharmacology.290 (1):29–36.doi:10.1016/0922-4106(95)90013-6.PMID7664822.
^abMillan MJ, Maiofiss L, Cussac D, Audinot V, Boutin JA, Newman-Tancredi A (November 2002). "Differential actions of antiparkinson agents at multiple classes of monoaminergic receptor. I. A multivariate analysis of the binding profiles of 14 drugs at 21 native and cloned human receptor subtypes".The Journal of Pharmacology and Experimental Therapeutics.303 (2):791–804.doi:10.1124/jpet.102.039867.PMID12388666.
^EP2508181A1, Bozik, Michael E.; Jr, Thomas Petzinger & Gribkoff, Valentin, "Compositions and Methods Of Using (R)-Pramipexole", issued 10 October 2012
^Hall ED, Andrus PK, Oostveen JA, Althaus JS, VonVoigtlander PF (December 1996). "Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neurons".Brain Research.742 (1–2):80–88.doi:10.1016/S0006-8993(96)00968-7.PMID9117424.
^Schneider CS, Mierau J (March 1987). "Dopamine autoreceptor agonists: resolution and pharmacological activity of 2,6-diaminotetrahydrobenzothiazole and an aminothiazole analogue of apomorphine".Journal of Medicinal Chemistry.30 (3):494–498.doi:10.1021/jm00386a009.PMID3820220.
^"Sifrol".www.boehringer-ingelheim.com. Retrieved27 February 2025.
^Chen Y, Li Y, Li C, Zhu D, Cheng O, Cui J (November 2022). "Dexmedetomidine alleviates pain in MPTP-treated mice by activating the AMPK/mTOR/NF-κB pathways in astrocytes".Neuroscience Letters.791 136933.doi:10.1016/j.neulet.2022.136933.PMID36283628.
^Rocha NP, Assis F, Scalzo PL, Vieira ÉL, Barbosa IG, de Souza MS, et al. (February 2018). "Reduced Activated T Lymphocytes (CD4+CD25+) and Plasma Levels of Cytokines in Parkinson's Disease".Molecular Neurobiology.55 (2):1488–1497.doi:10.1007/s12035-017-0404-y.PMID28176275.
^Lieberknecht V, Junqueira SC, Cunha MP, Barbosa TA, de Souza LF, Coelho IS, et al. (March 2017). "Pramipexole, a Dopamine D2/D3 Receptor-Preferring Agonist, Prevents Experimental Autoimmune Encephalomyelitis Development in Mice".Molecular Neurobiology.54 (2):1033–1045.doi:10.1007/s12035-016-9717-5.PMID26801190.
^Kang X, Liu L, Wang W, Wang Y (July 2023). "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".Journal of Stroke and Cerebrovascular Diseases.32 (7) 107142.doi:10.1016/j.jstrokecerebrovasdis.2023.107142.PMID37105127.
^Liu C, Sun X, Cai Y, Li D, Li B, Gao R, et al. (November 2022). "Pramipexole alleviates traumatic brain injury in rats through inhibiting necroptosis".Neuroscience Letters.791 136911.doi:10.1016/j.neulet.2022.136911.PMID36243204.
^DeBattista C, Solvason HB, Breen JA, Schatzberg AF (April 2000). "Pramipexole augmentation of a selective serotonin reuptake inhibitor in the treatment of depression".Journal of Clinical Psychopharmacology.20 (2):274–275.doi:10.1097/00004714-200004000-00029.PMID10770475.
^Zarate CA, Payne JL, Singh J, Quiroz JA, Luckenbaugh DA, Denicoff KD, et al. (July 2004). "Pramipexole for bipolar II depression: a placebo-controlled proof of concept study".Biological Psychiatry.56 (1):54–60.doi:10.1016/j.biopsych.2004.03.013.PMID15219473.
^Goldberg JF, Burdick KE, Endick CJ (March 2004). "Preliminary randomized, double-blind, placebo-controlled trial of pramipexole added to mood stabilizers for treatment-resistant bipolar depression".The American Journal of Psychiatry.161 (3):564–566.doi:10.1176/appi.ajp.161.3.564.PMID14992985.
^Goodwin GM, Martinez-Aran A, Glahn DC, Vieta E (November 2008). "Cognitive impairment in bipolar disorder: neurodevelopment or neurodegeneration? An ECNP expert meeting report".European Neuropsychopharmacology.18 (11):787–793.doi:10.1016/j.euroneuro.2008.07.005.PMID18725178.
^Li P, Wang T, Guo H, Liu Y, Zhao H, Ren T, et al. (July 2024). "Pramipexole improves depression-like behavior in diabetes mellitus with depression rats by inhibiting NLRP3 inflammasome-mediated neuroinflammation and preventing impaired neuroplasticity".Journal of Affective Disorders.356:586–596.doi:10.1016/j.jad.2024.04.073.PMID38657764.
^Herceg M, Nagy F, Pál E, Janszky J, Késmárky I, Komoly S, et al. (March 2012). "Pramipexole may be an effective treatment option in essential tremor".Clinical Neuropharmacology.35 (2):73–76.doi:10.1097/WNF.0b013e31824687bf.PMID22318193.
^Finkel MF (October 2000). "Pramipexole is a possible effective treatment for primary orthostatic tremor (shaky leg syndrome)".Archives of Neurology.57 (10):1519–1520.doi:10.1001/archneur.57.10.1519.PMID11030807.
