Pramipexole

Pramipexole

Clinical data
Pronunciation	/ˌpræmɪˈpɛksoʊl/
Trade names	Mirapex, Mirapexin, Sifrol, others
AHFS/Drugs.com	Monograph
MedlinePlus	a697029
License data	US  DailyMed:  Pramipexole
Pregnancy category	AU:B3 [1]
Routes of administration	By mouth
ATC code	N04BC05 ( WHO )
Legal status
Legal status	BR: Class C1 (Other controlled substances) [2] CA: ℞-only [3] US: ℞-only [4] [5] EU:Rx-only [6] [7] In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability	>90%
Protein binding	15%
Elimination half-life	8–12 hours
Excretion	Urine (90%), feces (2%)
Identifiers
IUPAC name (S)-N 6-propyl-4,5,6,7-tetrahydro-1,3-benzothiazole-2,6-diamine
CAS Number	104632-26-0  Y
PubChem CID	119570
IUPHAR/BPS	953
DrugBank	DB00413  Y
ChemSpider	106770  Y
UNII	83619PEU5T
KEGG	D05575  Y as salt:  D00559  Y
ChEBI	CHEBI:8356  Y
ChEMBL	ChEMBL301265  Y
CompTox Dashboard (EPA)	DTXSID6023496
ECHA InfoCard	100.124.761
Chemical and physical data
Formula	C10H17N3S
Molar mass	211.33 g·mol−1
3D model (JSmol)	Interactive image
SMILES n1c2c(sc1N)C[C@@H](NCCC)CC2
InChI InChI=1S/C10H17N3S/c1-2-5-12-7-3-4-8-9(6-7)14-10(11)13-8/h7,12H,2-6H2,1H3,(H2,11,13)/t7-/m0/s1 Y Key:FASDKYOPVNHBLU-ZETCQYMHSA-N Y
(verify)

Pramipexole, sold under the brand Mirapex among others, is a medication used to treat Parkinson's disease and restless legs syndrome. ^[8] In Parkinson's disease it may be used alone or together with levodopa. ^[8] It is taken by mouth. ^[8] Pramipexole is a dopamine agonist of the non-ergoline class. ^[8]

Pramipexole was approved for medical use in the United States in 1997. ^[8] It is available as a generic medication. ^[9] In 2022, it was the 193rd most commonly prescribed medication in the United States, with more than 2 million prescriptions. ^{[10] [11]}

Pramipexole (ball-and-stick) bound to the Dopamine D3 receptor (wire) PDB - 7CMU

Medical uses

Pramipexole is used in the treatment of Parkinson's disease and restless legs syndrome. ^[8] Safety in pregnancy and breastfeeding is unknown. ^[1]

A 2008 meta-analysis found that pramipexole was more effective than ropinirole in the treatment of restless legs syndrome. ^[12]

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. ^[13] Chronic administration of pramipexole may also result in desensitization of D₃ autoreceptors, leading to reduced dopamine transporter function. ^[14] Trials have shown mixed results for depression. ^[15]

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. ^[16]

Side effects

Common side effects of pramipexole include: ^{[17] [4] [5]}

• Headache
• Peripheral edema ^[18]
• 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" ^[19] such as compulsive gambling, punding, hypersexuality, and overeating, even in people without any prior history of these behaviors. ^{[20] [21] [22]} 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. ^[23] 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. ^[23]
• Augmentation: ^[a] 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" ^[24] and may include an earlier onset of symptoms during the day or a generalized increase in symptoms. ^{[25] [26] [27]}

Pharmacology

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

Activities of Pramipexole at various sites ^{[28] [29] [30] [31] [32] [33] [4] [5]}

Site	Affinity (Ki, nM)	Efficacy (Emax, %)	Action
D2S	3.3	130	Superagonist
D2L	3.9	99	Full agonist
D3	0.5	98	Full agonist
D4	3.9	91	Full agonist
Notes: Pramipexole also possesses lower affinity (500–10,000 nM) for the 5-HT1A, 5-HT1B, 5-HT1D, and α2-adrenergic receptors. [28] [34] It has negligible affinity (>10,000 nM) for the D1, D5, 5-HT2, α1-adrenergic, β-adrenergic, H1, and mACh receptors. [28] [34] All sites were assayed using human materials. [28] [29] Pramipexole is a superagonist at the presynaptic D2S receptor, S referring to a shorter amino acid sequence which desensitize overtime unlike postsynaptic D2L receptors.

Pramipexole Extended-Release 4.5mg Bottle 30 Count

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. ^[35] 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. ^[36]

Parkinson'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. ^[37] Pramipexole has also been shown to be protective against dopaminergic-related methamphetamine neurotoxicity. ^{[38] [39]}

Plasma Concentration of 0.25mg PO after a single dose.

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 ${\displaystyle \infty }$ by 50% and increase the t_1/2 by 40%. ^{[40] [41]}

Society and culture

Brand names

Brand names include Mirapex, Mirapex ER, Mirapexin, Sifrol, Glepark, and Oprymea.^{[ citation needed ]}

Research

Pramipexole has been evaluated for the treatment of sexual dysfunction experienced by some users of selective serotonin reuptake inhibitor antidepressants. ^[42] Pramipexole has shown effects on pilot studies in a placebo-controlled proof of concept study in bipolar disorder. ^{[43] [44] [45]} It is also being investigated for the treatment of clinical depression, fibromyalgia ^{[46] [47] [48]} , essential tremor ^{[49] [50]} and primary orthostatic tremor ('shaky leg syndrome') ^[51] .

Derivatives

Derivatives of Pramipexole include CJ-998, CJ-1037, CJ-1638, CJ-1639, ^[52] D-264, D-440, ^[53] and D-512. ^[53]

Explanatory notes

1. 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).

References

1. "Pramipexole Pregnancy and Breastfeeding Warnings". Drugs.com. Archived from the original on 22 March 2019. Retrieved 3 March 2019.
2. Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
3. "Product monograph brand safety updates". Health Canada. February 2024. Retrieved 24 March 2024.
4. "Mirapex- pramipexole dihydrochloride tablet". DailyMed. 1 March 2020. Archived from the original on 18 October 2020. Retrieved 17 October 2020.
5. "Mirapex ER- pramipexole dihydrochloride tablet, extended release". DailyMed. 5 February 2020. Archived from the original on 21 October 2020. Retrieved 17 October 2020.
6. "Sifrol EPAR". European Medicines Agency. 17 November 2009. Archived from the original on 18 October 2020. Retrieved 17 October 2020.
7. "Mirapexin EPAR". European Medicines Agency. 17 November 2009. Archived from the original on 18 October 2020. Retrieved 17 October 2020.
8. "Pramipexole Dihydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Archived from the original on 3 April 2019. Retrieved 22 March 2019.
9. British national formulary : BNF 76 (76 ed.). Pharmaceutical Press. 2018. pp. 417–418. ISBN   9780857113382.
10. "The Top 300 of 2022". ClinCalc. Archived from the original on 30 August 2024. Retrieved 30 August 2024.
11. "Pramipexole Drug Usage Statistics, United States, 2013 - 2022". ClinCalc. Retrieved 30 August 2024.
12. 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. PMID   18226947.
13. Chernoloz O, El Mansari M, Blier P (February 2012). "Long-term administration of the dopamine D3/2 receptor agonist pramipexole increases dopamine and serotonin neurotransmission in the male rat forebrain". Journal of Psychiatry & Neuroscience. 37 (2): 113–121. doi:10.1503/jpn.110038. PMC   3297071 . PMID   22023785.
14. Castro-Hernández J, Afonso-Oramas D, Cruz-Muros I, Salas-Hernández J, Barroso-Chinea P, Moratalla R, et al. (February 2015). "Prolonged treatment with pramipexole promotes physical interaction of striatal dopamine D3 autoreceptors with dopamine transporters to reduce dopamine uptake". Neurobiology of Disease. 74: 325–335. doi:10.1016/j.nbd.2014.12.007. PMID   25511804.
15. Fawcett J, Rush AJ, Vukelich J, Diaz SH, Dunklee L, Romo P, et al. (February 2016). "Clinical Experience With High-Dosage Pramipexole in Patients With Treatment-Resistant Depressive Episodes in Unipolar and Bipolar Depression". The American Journal of Psychiatry. 173 (2): 107–111. doi: 10.1176/appi.ajp.2015.15060788 . PMID   26844792.
16. 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. PMID   27449005.
17. "MedlinePlus Drug Information: Pramipexole (Systemic)". United States National Library of Medicine. Archived from the original on 26 September 2006. Retrieved 27 September 2006.
18. Tan EK, Ondo W (May 2000). "Clinical characteristics of pramipexole-induced peripheral edema". Archives of Neurology. 57 (5): 729–732. doi: 10.1001/archneur.57.5.729 . PMID   10815140.
19. 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. PMID   32272129. ... 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.
20. Bostwick JM, Hecksel KA, Stevens SR, Bower JH, Ahlskog JE (April 2009). "Frequency of new-onset pathologic compulsive gambling or hypersexuality after drug treatment of idiopathic Parkinson disease". Mayo Clinic Proceedings. 84 (4): 310–316. doi:10.4065/84.4.310. PMC   2665974 . PMID   19339647.
21. Moore TJ, Glenmullen J, Mattison DR (December 2014). "Reports of pathological gambling, hypersexuality, and compulsive shopping associated with dopamine receptor agonist drugs". JAMA Internal Medicine. 174 (12): 1930–1933. doi: 10.1001/jamainternmed.2014.5262 . PMID   25329919.
22. 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. PMID   18787882.
23. Elliott C. "The Degradation Drug". The American Scholar. Archived from the original on 15 September 2022. Retrieved 15 September 2022.
24. 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. PMID   29756335. ... the specific goals of the current review were to … separately identify the [restless legs syndrome]-specific side effect, which is augmentation.
25. "Pramipexole Monograph for Professionals". Drugs.com. Archived from the original on 25 November 2021. Retrieved 11 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.
26. Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, et al. (December 2016). "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". Neurology. 87 (24): 2585–2593. doi:10.1212/WNL.0000000000003388. PMC   5206998 . PMID   27856776.
27. 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. PMID   30411165. … augmentation of the [restless legs syndrome] symptoms is a major limitation of oral dopaminergic therapy.
28. Kvernmo 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. PMID   16982285.
29. Newman-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. PMID   12388667.
30. 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. PMID   7664822.
31. "PDSP Ki Database Pramipexole Query". PDSP Ki Database. UNC. Archived from the original on 11 October 2023. Retrieved 11 July 2022.
32. "Pramipexole dihydrochloride characteristics". Bio-techne. Archived from the original on 12 July 2022. Retrieved 11 July 2022.
33. Coldwell MC, Boyfield I, Brown T, Hagan JJ, Middlemiss DN (August 1999). "Comparison of the functional potencies of ropinirole and other dopamine receptor agonists at human D2(long), D3 and D4.4 receptors expressed in Chinese hamster ovary cells". British Journal of Pharmacology. 127 (7): 1696–1702. doi:10.1038/sj.bjp.0702673. PMC   1566138 . PMID   10455328.
34. Millan 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. PMID   12388666.
35. Weber M, Chang WL, Breier M, Ko D, Swerdlow NR (December 2008). "Heritable strain differences in sensitivity to the startle gating-disruptive effects of D2 but not D3 receptor stimulation". Behavioural Pharmacology. 19 (8): 786–795. doi:10.1097/FBP.0b013e32831c3b2b. PMC   3255557 . PMID   19020413.
36. Chang WL, Weber M, Breier MR, Saint Marie RL, Hines SR, Swerdlow NR (February 2012). "Stereochemical and neuroanatomical selectivity of pramipexole effects on sensorimotor gating in rats". Brain Research. 1437: 69–76. doi:10.1016/j.brainres.2011.12.007. PMC   3268831 . PMID   22227455.
37. Samuels ER, Hou RH, Langley RW, Szabadi E, Bradshaw CM (November 2007). "Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteers". British Journal of Clinical Pharmacology. 64 (5): 591–602. doi:10.1111/j.1365-2125.2007.02938.x. PMC   2203276 . PMID   17578485.
38. 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. PMID   9117424.
39. "Pramipexole". Drug Bank.
40. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/020667s025lbl.pdf
41. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/022421s023lbl.pdf
42. 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. PMID   10770475.
43. 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. PMID   15219473.
44. 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. PMID   14992985.
45. 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. PMID   18725178.
46. Lattanzi L, Dell'Osso L, Cassano P, Pini S, Rucci P, Houck PR, et al. (October 2002). "Pramipexole in treatment-resistant depression: a 16-week naturalistic study". Bipolar Disorders. 4 (5): 307–314. doi:10.1034/j.1399-5618.2002.01171.x. PMID   12479663.
47. Cassano P, Lattanzi L, Soldani F, Navari S, Battistini G, Gemignani A, et al. (2004). "Pramipexole in treatment-resistant depression: an extended follow-up". Depression and Anxiety. 20 (3): 131–138. doi: 10.1002/da.20038 . PMID   15549689.
48. Holman AJ, Myers RR (August 2005). "A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications". Arthritis and Rheumatism. 52 (8): 2495–2505. doi: 10.1002/art.21191 . PMID   16052595.
49. 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. ISSN   0362-5664.
50. Kosmowska B, Wardas J, Głowacka U, Ananthan S, Ossowska K (January 2016). "Pramipexole at a Low Dose Induces Beneficial Effect in the Harmaline‐induced Model of Essential Tremor in Rats". CNS Neuroscience & Therapeutics. 22 (1): 53–62. doi:10.1111/cns.12467. ISSN   1755-5930. PMC   6492867 . PMID   26459182.
51. Finkel MF (1 October 2000). "Pramipexole Is a Possible Effective Treatment for Primary Orthostatic Tremor (Shaky Leg Syndrome)". Archives of Neurology. 57 (10). doi:10.1001/archneur.57.10.1519. ISSN   0003-9942.
52. Chen J, Collins GT, Levant B, Woods J, Deschamps JR, Wang S (August 2011). "CJ-1639: A Potent and Highly Selective Dopamine D3 Receptor Full Agonist". ACS Medicinal Chemistry Letters. 2 (8): 620–625. doi:10.1021/ml200100t. PMC   3224040 . PMID   22125662.
53. Santra S, Xu L, Shah M, Johnson M, Dutta A (October 2013). "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". ACS Chemical Neuroscience. 4 (10): 1382–1392. doi:10.1021/cn400106n. PMC   3798991 . PMID   23906010.