Ropinirole

Last updated

Ropinirole
Ropinirole-2D-Skeletal-Formula.png
RopiniroleMV.png
Clinical data
Trade names Requip, Repreve, Ronirol, others
Other namesSK&F-101468; SK&F101468; SKF-101468; SKF101468
AHFS/Drugs.com Monograph
MedlinePlus a698013
License data
Routes of
administration 		By mouth
ATC code
Legal status
Legal status
  • BR: Class C1 (Other controlled substances) [1]
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 50% [2]
Metabolism Liver (CYP1A2) [2]
Elimination half-life 5-6 hours [2]
Identifiers
  • 4-[2-(Dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.110.353 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C16H24N2O
Molar mass 260.381 g·mol−1
3D model (JSmol)
  • O=C2Nc1cccc(c1C2)CCN(CCC)CCC
  • InChI=1S/C16H24N2O/c1-3-9-18(10-4-2)11-8-13-6-5-7-15-14(13)12-16(19)17-15/h5-7H,3-4,8-12H2,1-2H3,(H,17,19) Yes check.svgY
  • Key:UHSKFQJFRQCDBE-UHFFFAOYSA-N Yes check.svgY
   (verify)

Ropinirole, sold under the brand name Requip among others, is a medication used to treat Parkinson's disease (PD) and restless legs syndrome (RLS). [3] It is taken by mouth. [4]

Contents

Common side effects include sleepiness, vomiting, and dizziness. [4] Serious side effects may include pathological gambling, hypersexuality, low blood pressure with standing and hallucinations. [3] [4] Use in pregnancy and breastfeeding is of unclear safety. [5] It is a dopamine agonist and works by triggering dopamine D2 receptors. [4]

It was approved for medical use in the United States in 1997. [4] It is available as a generic medication. [3] In 2023, it was the 212th most commonly prescribed medication in the United States, with more than 2 million prescriptions. [6] [7]

Medical uses

Ropinirole is prescribed for mainly Parkinson's disease, restless legs syndrome, and extrapyramidal symptoms. It can also reduce the side effects caused by selective serotonin reuptake inhibitors, including Parkinsonism syndrome as well as sexual dysfunction and erectile dysfunction caused by either SSRIs [8] or antipsychotics.

A 2008 meta-analysis found that ropinirole was less effective than pramipexole in the treatment of restless legs syndrome. [9]

Side effects

Ropinirole can cause nausea, dizziness, hallucinations, orthostatic hypotension, and sudden sleep attacks during the daytime. Unusual side effects specific to D3 agonists such as ropinirole and pramipexole can include hypersexuality, punding and compulsive gambling, even in patients without a history of these behaviours. [10]

Ropinirole is also known to cause an effect known as "augmentation" when used to treat restless legs syndrome, where over time treatment with dopamine agonists will cause restless legs syndrome symptoms to become more severe. This usually leads to constant dosage increases in an attempt to offset the symptom progression. Symptoms will return to the level of severity they were experienced at before treatment was initiated if the drug is stopped; however, both ropinirole and pramipexole are known to cause painful withdrawal effects when treatment is stopped and the process of taking a patient who has been using the medication long-term off these drugs is often very difficult and should be supervised by a medical professional. [11]

Pharmacology

Pharmacodynamics

Binding Table [12]
TargetKi (nM)IA%Action
D1>10,000?Agonist
D23.7100%Full Agonist
D32.997%Full Agonist
D47.881%Partial Agonist
D5>10,000?Agonist
https://doi.org/10.1093/nar/gkae300 https://pubs.acs.org/doi/10.1021/acs.jcim.3c00054 [PDB ID: 8IRS] [Rendered with SwissDrugDesign Software] ROPINRIOLE D2 DOCKING.png
https://doi.org/10.1093/nar/gkae300https://pubs.acs.org/doi/10.1021/acs.jcim.3c00054 [PDB ID: 8IRS] [Rendered with SwissDrugDesign Software]

Ropinirole acts as a D2, D3, and D4 dopamine receptor agonist with highest affinity for D3, which are mostly found in the limbic areas. [13] It is weakly active at the 5-HT2, and α2 receptors and is said to have virtually no affinity for the 5-HT1, GABA, mAChRs, α1-, and β-adrenoreceptors. [14] It is a potent agonist of the 5-HT2B receptor, but shows biased agonism at this receptor and does not appear to pose a risk of cardiac valvulopathy. [15] [16] The comprehensive receptor interactions of ropinirole have been described. [17] [18] [19] [20] [21] [22]

Ropinirole produces marked hypolocomotion at lower doses (1–50 mg/kg i.p.) and causes hyperlocomotion at higher doses (100 mg/kg i.p.) in rodents. [23] The former effect is thought to be mediated by activation of inhibitory presynaptic dopamine autoreceptors and reduced dopamine release, while the latter action is thought to be due to stimulation of postsynaptic dopamine receptors. [23] Activation of postsynaptic dopamine D2 receptors is thought to be involved in the antiparkinsonian effects of dopamine D2 receptor agonists like ropinrole. [23]

Pharmacokinetics

Major metabolites in vivo formed by CYP1A2-mediated metabolism of ropinirole. Ropinirole Metabolites.png
Major metabolites in vivo formed by CYP1A2-mediated metabolism of ropinirole.

Ropinirole is metabolized primarily by cytochrome P450 CYP1A2 to form two metabolites; SK&F-104557 and SK&F-89124, both of which are renally excreted, [24] and at doses higher than clinical, is also metabolized by CYP3A4. At doses greater than 24 mg, CYP2D6 may be inhibited, although this has been tested only in vitro. [2]

7-Hydroxyropinirole (SK&F-89124), a major metabolite of ropinirole in rats but minor metabolite in humans (<5% of dose), is a highly potent dopamine receptor agonist with antiparkinsonian activity similarly to ropinirole. [25] [26] [27] [28] [29] It has been reported to be 30-fold more potent than ropinirole as a dopamine D2 receptor agonist in vitro . [30] [31] However, ropinirole and 7-hydroxyropinirole were equipotent in terms of antiparkinsonian activity in rodents in vivo . [29] 7-Hydroxyropinirole is said to be the only metabolite of ropinirole known to possess significant dopaminergic activity in vivo, although other ropinirole metabolites have also been found to have dopaminergic activity. [32] [27] [29]

Chemistry

Ropinirole is a partial ergoline and the LSD metabolite 2-oxo-LSD contains most of ropinirole within its chemical structure. [33] A notable analogue of ropinirole is DPAI (2-desoxo-2-ene-ropinirole). [34] [35] [36]

History

Ropinirole was first described in the scientific literature by 1985. [25] [37] [38] [39] [40]

Society and culture

It is manufactured by GlaxoSmithKline (GSK), Mylan Pharmaceuticals, Cipla, Dr. Reddy's Laboratories and Sun Pharmaceutical. The discovery of the drug's utility in restless legs syndrome has been used as an example of successful drug repurposing. [41]

Lawsuit

In November 2012, GlaxoSmithKline was ordered by a Rennes appeals court to pay Frenchman Didier Jambart 197,000 euros ($255,824); Jambart had taken ropinirole from 2003 to 2010 and exhibited risky hypersexual behavior and gambled excessively until stopping the medication. [42] This behavior displayed is characteristic of Dopamine Dysregulation Syndrome. [43]

See also

References

  1. ↑ 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.
  2. 1 2 3 4 Tompson DJ, Vearer D (December 2007). "Steady-state pharmacokinetic properties of a 24-hour prolonged-release formulation of ropinirole: results of two randomized studies in patients with Parkinson's disease". Clinical Therapeutics. 29 (12): 2654–2666. doi:10.1016/j.clinthera.2007.12.010. PMID   18201581.
  3. 1 2 3 British National Formulary (76th ed.). Pharmaceutical Press. 2018. pp. 419–420. ISBN   978-0-85711-338-2.
  4. 1 2 3 4 5 "Ropinirole Hydrochloride Monograph for Professionals". Drugs.com. American Society of Health-System Pharmacists. Retrieved 3 March 2019.
  5. ↑ "Ropinirole Pregnancy and Breastfeeding Warnings". Drugs.com. Retrieved 3 March 2019.
  6. ↑ "The Top 300 of 2023". ClinCalc. Archived from the original on 12 August 2025. Retrieved 12 August 2025.
  7. ↑ "Ropinirole Drug Usage Statistics, United States, 2013 - 2023". ClinCalc. Retrieved 20 August 2025.
  8. ↑ Clinical trial number NCT00334048 at ClinicalTrials.gov - "Treating Sexual Dysfunction From SSRI Medication: a Study Comparing Requip CR to Placebo"
  9. ↑ 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.
  10. ↑ 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.
  11. ↑ "What is Augmentation?" (PDF). Austin, Texas: Restless Legs Syndrome (RLS) Foundation. Archived from the original (PDF) on 9 May 2018. Retrieved 8 May 2018.
  12. ↑ Coldwell MC, Boyfield I, Brown T, Hagan JJ, Middlemiss DN (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.
  13. ↑ Shill HA, Stacy M (2009). "Update on ropinirole in the treatment of Parkinson's disease". Neuropsychiatric Disease and Treatment. 5: 33–36. PMC   2695212 . PMID   19557097.
  14. ↑ Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, et al. (January 1991). "Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist". Pharmacology, Biochemistry, and Behavior. 38 (1): 147–154. doi:10.1016/0091-3057(91)90603-Y. PMID   1673248. S2CID   26842270.
  15. ↑ Bender AM, Parr LC, Livingston WB, Lindsley CW, Merryman WD (August 2023). "2B Determined: The Future of the Serotonin Receptor 2B in Drug Discovery". J Med Chem. 66 (16): 11027–11039. doi:10.1021/acs.jmedchem.3c01178. PMC   11073569 . PMID   37584406. S2CID   260924858. Functionally Biased Agonists. Conversely, a compound presenting as an agonist in 5-HT2B functional assays does not necessarily pose a risk for valvulopathy. In 5-HT2B calcium flux assays, certain known VHD-associated compounds displayed an agonist profile comparable to that of ropinirole, an approved treatment for Parkinson's disease (PD) and restless leg syndrome.122 Because ropinirole is not known to be associated with VHD or similar cardiopathies, it is thought that calcium flux may not be the optimal assay for screening 5-HT2B agonists for potential VHD-related risks. In additional readouts of 5-HT2B receptor activation (calcium-sensitive NFAT-mediated transcription of a β-lactamase reporter gene, accumulation of InsPs in LiCl-treated cells, recruitment of β-arrestin to agonist-occupied receptors, and phosphorylation of the extracellular signal-regulated kinase ERK2), ropinirole was found to be "distinct from the seven known valvulopathic 5- HT2B receptor agonists [studied] in that it is much less potent, albeit not less efficacious, than the VHD-associated drugs in all but one of the 5-HT2B receptor functional assays employed." 66
  16. ↑ Huang XP, Setola V, Yadav PN, Allen JA, Rogan SC, Hanson BJ, et al. (October 2009). "Parallel functional activity profiling reveals valvulopathogens are potent 5-hydroxytryptamine(2B) receptor agonists: implications for drug safety assessment". Mol Pharmacol. 76 (4): 710–22. doi:10.1124/mol.109.058057. PMC   2769050 . PMID   19570945.
  17. ↑ "PDSP Database". UNC (in Zulu). Retrieved 29 January 2026.
  18. ↑ Liu T. "BindingDB BDBM50020680 4-[2-(dipropylamino)ethyl]-1,3-dihydro-2H-indol-2-one::CHEMBL589::ROPINIROLE". BindingDB. Retrieved 29 January 2026.
  19. ↑ Kvernmo T, Härtter S, Burger E (August 2006). "A review of the receptor-binding and pharmacokinetic properties of dopamine agonists". Clin Ther. 28 (8): 1065–1078. doi:10.1016/j.clinthera.2006.08.004. PMID   16982285.
  20. ↑ Kvernmo T, Houben J, Sylte I (2008). "Receptor-binding and pharmacokinetic properties of dopaminergic agonists". Curr Top Med Chem. 8 (12): 1049–1067. doi:10.2174/156802608785161457. PMID   18691132.
  21. ↑ 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". J Pharmacol Exp Ther. 303 (2): 791–804. doi:10.1124/jpet.102.039867. PMID   12388666.
  22. ↑ Millan MJ, Cussac D, Gobert A, Lejeune F, Rivet JM, Mannoury La Cour C, et al. (June 2004). "S32504, a novel naphtoxazine agonist at dopamine D3/D2 receptors: I. Cellular, electrophysiological, and neurochemical profile in comparison with ropinirole". J Pharmacol Exp Ther. 309 (3): 903–920. doi:10.1124/jpet.103.062398. PMID   14978194.
  23. 1 2 3 Matheson AJ, Spencer CM (July 2000). "Ropinirole: a review of its use in the management of Parkinson's disease". Drugs. 60 (1): 115–137. doi:10.2165/00003495-200060010-00007. PMID   10929932.
  24. ↑ Tompson D, Hewens D, Earl N, Oliveira D, Taubel J, Swan S, et al. (7–11 June 2009). An open-label, parallel-group, repeat-dose study to investigate the effects of end-stage renal disease and haemodialysis on the pharmacokinetics of ropinirole] (PDF). 13th International Congress of Parkinson’s Disease and Movement Disorders. Paris, France. Archived from the original (PDF) on 17 March 2012.
  25. 1 2 Okano H, Yasuda D, Fujimori K, Morimoto S, Takahashi S (February 2020). "Ropinirole, a New ALS Drug Candidate Developed Using iPSCs". Trends Pharmacol Sci. 41 (2): 99–109. doi:10.1016/j.tips.2019.12.002. PMID   31926602. Before ROPI was first reported in 1985 [27], 7-hydroxyropinirole was identified as a highly potent dopamine agonist [28,29]. 7-Hydroxyropinirole has also been identified as a metabolite of ROPI in humans. [...] N,N-di-n-Propyldopamine is a lipophilic derivative of dopamine. By conversion of the monocyclic ring of N,N-di-n-propyldopamine to a bicyclic oxindole skeleton (bioisostere of phenol), 7-hydroxyropinirole was developed. Surprisingly, compared with that of N,N-di-npropyldopamine, the EC50 of 7-hydroxyropinirole for the dopamine D2 receptor (D2R) was greatly improved. ROPI does not have a 7-hydroxy group and its EC50 for D2R is higher than that of N,N-di-n-propyldopamine; nevertheless ROPI was ultimately selected as a clinical drug candidate.
  26. ↑ Ramji JV, Keogh JP, Blake TJ, Broom C, Chenery RJ, Citerone DR, et al. (March 1999). "Disposition of ropinirole in animals and man". Xenobiotica. 29 (3): 311–325. doi:10.1080/004982599238696. PMID   10219970. In both animals and man, ropinirole was extensively metabolized. In the rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole. In mouse, monkey and man, the major pathway was via N-depropylation. The N-despropyl metabolite was metabolized further to form 7-hydroxy and carboxylic acid derivatives. Metabolites formed in all species were generally metabolized further by glucuronidation. 7-Hydroxy ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo. [...] Brain extracts were shown to contain ropinirole and its 7-hydroxy metabolite (SK&F-89124 ; Figure 2). [...] In rat, the major metabolic pathway was via hydroxylation of the aromatic ring to form 7-hydroxy ropinirole (SK&F-89124). In mouse, monkey and man, the major pathway was via N-depropylation to form SK&F-104557, which was further metabolized, to a limited extent, to 7-hydroxy SK&F-104557 (SK&F-96990) and a carboxylic acid derivative of SK&F-104557 (SK&F-97930). Metabolites formed by either pathway were then generally metabolized further by glucuronidation in all species. SK&F-89124 is the only metabolite of ropinirole shown to possess significant dopamine agonist activity in an in vivo model of Parkinson's disease (Reavill et al., unpublished data).
  27. 1 2 Contin M, Riva R, Albani F, Baruzzi A (2000). "Pharmacokinetic Optimisation of Dopamine Receptor Agonist Therapy for Parkinson??s Disease:". CNS Drugs. 14 (6): 439–455. doi:10.2165/00023210-200014060-00003. ISSN   1172-7047. The major metabolic pathway in humans is via N-depropylation;[55] the N-despropyl metabolite accounts for 35 to 40% of the oral dose in human urine. 7-hydroxy ropinirole, the only metabolite of ropinirole that is thought to have significant dopamine agonist activity in vivo, [55] accounts for less than 5% of the dose. The potential contribution of 7-hydroxy ropinirole to the clinical effects of the parent drug is unknown.
  28. ↑ Hieble JP, Sulpizio AC, Sarau HM, Flaim KE, Blumberg AL, McCafferty JP, et al. (1989). "SK&F 89124, a potent and selective agonist at prejunctional dopamine receptors". Fundam Clin Pharmacol. 3 (6): 621–642. doi:10.1111/j.1472-8206.1989.tb00464.x. PMID   2575569.
  29. 1 2 3 Reavill C, Boyfield I, Coldwell M, Nelson P (September 2000). "Comparative pharmacological study of ropinirole (SKF-101468) and its metabolites in rats". J Pharm Pharmacol. 52 (9): 1129–1235. doi:10.1211/0022357001774895. PMID   11045894.
  30. ↑ Hieble JP (1987). "Chapter 11 Peripheral Actions of Dopamine Receptor Agonists". Annual Reports in Medicinal Chemistry. Elsevier. p. 107–116. doi:10.1016/s0065-7743(08)61159-8. ISSN   0065-7743. SK&F 101468 is hydroxylated vivo to form SK&F 89124, which is 30-fold more potent as a DA2 agonist (77); hence, although SK&F 101468 has intrinsic agonist activity at the DA2 receptor, being only two-fold less potent than dopamine as an inhibitor of adrenergic neurotransmission in the isolated rabbit ear artery (76), the majority of its in vivo activity may result from an active metabolite.
  31. ↑ Mico BA, Swagzdis JE, Federowicz DA, Straub K (October 1986). "Functional group metabolism of dopamine-2 agonists: conversion of 4-(2-di-n-propylaminoethyl)-2-(3H)-indolone to 4-(2-di-n-propylaminoethyl)-7-hydroxy-2-(3H)-indolone". J Pharm Sci. 75 (10): 929–933. doi:10.1002/jps.2600751003. PMID   3795021. 4-(2-Di-n-propylaminoethyl)-7-hydroxy-2-(3~)-indolone was found in the plasma of rats, dogs, and monkeys treated with 3. As a D2-agonist, 1 is 30 times more potent than 3 in in vitro studies.1.3 The metabolism of 3 to 1 may contribute to the in vivo pharmacologic effect of 3. In dogs and monkeys (Figs. 5 and 6) the concentrations of 1 are about 10-fold lower than those of 3 and decline in parallel with 3.
  32. ↑ Deleu D, Northway MG, Hanssens Y (2002). "Clinical pharmacokinetic and pharmacodynamic properties of drugs used in the treatment of Parkinson's disease". Clin Pharmacokinet. 41 (4): 261–309. doi:10.2165/00003088-200241040-00003. PMID   11978145. 7-Hydroxy-ropinirole is the only metabolite of ropinirole previously shown to possess significant dopamine agonist activity in vivo.
  33. ↑ Sit SY (August 2000). "Dopamine agonists in the treatment of Parkinson s disease past, present and future". Curr Pharm Des. 6 (12): 1211–1248. doi:10.2174/1381612003399581. PMID   10903391.
  34. ↑ Clemens, J. A., Kornfeld, E. C., Phebus, L. A., Shaar, C. J., Smalstig, E. B., Cassady, J. M., ... & Kelly, E. (1982). Dopaminergic Agents Related to Ergolines. In The Chemical Regulation of Biological Mechanisms: The Proceedings of the 1st Medicinal Chemistry Symposium, Cambridge, England, 27th-30 September 1981 (Vol. 42, p. 167). London: Royal Society of Chemistry. https://archive.org/details/chemicalregulati0000medi/page/167/mode/1up
  35. ↑ David E. Nichols (29 June 1983). "The Development of Novel Dopamine Agonists". Dopamine Receptors. Vol. 224. Washington, D.C.: American Chemical Society. pp. 201–222. doi:10.1021/bk-1983-0224.ch009. ISBN   978-0-8412-0781-3. The situation seems further confounded by the reports (13) of dopaminergic activity for the 4-substituted aminoethylindole DPAI, IX. However, the delayed onset of action reported by Cannon et al . (13) for this compound, as well as a weak in vitro action (14), lead to the possibility that DPAI may be metabolically activated by hydroxylation at the 6-position. This is a common transformation for indoles. Indeed, lergotrile is hydroxylated at the corresponding 13 position to yield a metabolite which is an order of magnitude more potent than lergotrile itself (15).
  36. ↑ Clemens JA, Fuller RW, Phebus LA, Smalstig EB, Hynes MD, Cassady JM, et al. (March 1984). "Stimulation of presynaptic dopamine autoreceptors by 4-(2-di-n-propylaminoethyl) indole (DPAI)". Life Sci. 34 (11): 1015–1022. doi:10.1016/0024-3205(84)90014-6. PMID   6422174.
  37. ↑ Gallagher G, Lavanchy PG, Webster CA, Wilson JW, Hieble JP, DeMarinis RM (October 1985). "4-[2-(Di-n-propylamino)ethyl]-2(3H)-indolone: a prejunctional dopamine receptor agonist". J Med Chem. 28 (10): 1533–1536. doi:10.1021/jm00148a028. PMID   4045928.
  38. ↑ Eden RJ, Wallduck MS, Patel B, Owen DA (January 1990). "Autonomic and haemodynamic responses to SK & F 101468 (ropinirole), a DA2 agonist, in anaesthetised cats". Eur J Pharmacol. 175 (3): 333–340. doi:10.1016/0014-2999(90)90572-n. PMID   1969802.
  39. ↑ Eden RJ, Costall B, Domeney AM, Gerrard PA, Harvey CA, Kelly ME, et al. (January 1991). "Preclinical pharmacology of ropinirole (SK&F 101468-A) a novel dopamine D2 agonist". Pharmacol Biochem Behav. 38 (1): 147–154. doi:10.1016/0091-3057(91)90603-y. PMID   1673248.
  40. ↑ Kleedorfer B, Stern GM, Lees AJ, Bottomley JM, Sree-Haran N (October 1991). "Ropinirole (SK and F 101468) in the treatment of Parkinson's disease". J Neurol Neurosurg Psychiatry. 54 (10): 938. doi:10.1136/jnnp.54.10.938. PMC   1014589 . PMID   1683897.
  41. ↑ Lipp E (1 August 2008). "Novel Approaches to Lead Optimization". Genetic Engineering & Biotechnology News. Vol. 28, no. 14. p. 20. Retrieved 28 September 2008.
  42. ↑ Wong C (29 November 2012). "Court Rules Parkinson's Drug Turned Straight Patient Into A Gay Sex Addict". Huffington Post.
  43. ↑ Klepitskaya O (2010). "Dopamine Dysregulation Syndrome". Encyclopedia of Movement Disorders. pp. 323–326. doi:10.1016/B978-0-12-374105-9.00538-4. ISBN   978-0-12-374105-9.
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