Chemistry:Rotigotine

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Short description: Dopamine agonist medication
Rotigotine
Rotigotine.svg
Clinical data
Trade namesNeupro, Leganto
AHFS/Drugs.comMonograph
MedlinePlusa607059
License data
Pregnancy
category
  • AU: B3
Routes of
administration
Transdermal patch
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • BR: Class C1 (Other controlled substances)
  • US: ℞-only
  • EU: Rx-only [1]
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability37% (transdermal)
Protein binding92%
MetabolismLiver (CYP-mediated)
Elimination half-life5–7 hours
ExcretionUrine (71%), Feces (23%)
Identifiers
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
Chemical and physical data
FormulaC19H25NOS
Molar mass315.48 g·mol−1
3D model (JSmol)
 ☒N☑Y (what is this?)  (verify)

Rotigotine, sold under the brand name Neupro among others, is a dopamine agonist of the non-ergoline class of medications indicated for the treatment of Parkinson's disease and restless legs syndrome.[2][3] It is formulated as a once-daily transdermal patch which provides a slow and constant supply of the drug over the course of 24 hours.[2]

Like other dopamine agonists, rotigotine has been shown to possess antidepressant effects and may be useful in the treatment of depression as well.[4]

History

Initially developed at the University of Groningen in 1985 as N-0437,[5] Aderis Pharmaceuticals acquired rotigotine and continued development toward commercialization.[citation needed] In 1998, Aderis globally out-licensed rotigotine for development and commercialization to Schwarz Pharma,[6] which firm was acquired by UCB S.A. in 2006. Schwarz completed acquisition of full rights to rotigotine from Aderis as of 2005.[7]

The drug was approved by the European Medicines Agency (EMA) for use in Europe in 2006.[1] In 2007, the Neupro patch was approved by the Food and Drug Administration (FDA).[8] It became the first transdermal treatment of Parkinson's disease in the United States.[citation needed] In 2008, Schwarz Pharma recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism. FDA also suspended its marketing authorization after crystal formation was noted in some patches.[9] The patch was reformulated, and was reintroduced in the United States in 2012.[10]

Rotigotine was authorized as a treatment for restless legs syndrome in August 2008.[3]

Side effects

General side effects for rotigotine may include constipation, dyskinesia, nausea, vomiting, dizziness, fatigue, insomnia, somnolence, confusion, and hallucinations.[11][12] More serious complications can include psychosis and impulse control disorders like hypersexuality, punding, and pathological gambling.[13] Mild adverse skin reactions at the patch application site may also occur.[2][12]

Pharmacology

Rotigotine acts as a non-selective agonist of the dopamine D1, D2, D3, and, to a lesser extent, D4 and D5 receptors, with highest affinity for the D3 receptor.[14] In terms of affinity, rotigotine has 10-fold selectivity for the D3 receptor over the D2, D4, and D5 receptors and 100-fold selectivity for the D3 receptor over the D1 receptor.[14] In functional studies however, rotigotine behaves as a full agonist of D1, D2, and D3 with similar potencies (EC50).[14] Its ability to activate both D1-like and D2-like receptors is similar to the case of apomorphine (which notably has greater efficacy in the treatment of Parkinson's disease than D2-like-selective agonists but has suboptimal pharmacokinetic properties) and pergolide but unlike pramipexole and ropinirole.[14]

In vitro receptor binding profile of rotigotine[15]
Receptor Ki (nM)
D1 83
D2 13.5
D3 0.71
D4.2 3.9
D4.4 15
D4.7 5.9
D5 5.4
α1A 176
α1B 273
α2A 338
α2B 27
α2C 135
5-HT1A 30
5-HT7 86
H1 330

All affinities listed were assayed using human materials except that for α2B-adrenergic which was done with NG 108–15 cells. Rotigotine behaves as a partial or full agonist (depending on the assay) at all dopamine receptors listed, as an antagonist at the α2B-adrenergic receptor, and as a partial agonist at the 5-HT1A receptor.[15] Though it has affinity for a large number of sites as shown above, at clinical doses rotigotine behaves mostly as a selective D1-like (D1, D5) and D2-like (D2, D3, D4) receptor agonist, with its α2B-adrenergic and 5-HT1A activity also possibly having some minor relevance.

References

  1. 1.0 1.1 "Neupro EPAR". 17 September 2018. https://www.ema.europa.eu/en/medicines/human/EPAR/neupro. 
  2. 2.0 2.1 2.2 "Transdermal rotigotine: a clinically innovative dopamine-receptor agonist for the management of Parkinson's disease". Pharmacotherapy 29 (12): 1452–1467. December 2009. doi:10.1592/phco.29.12.1452. PMID 19947805. 
  3. 3.0 3.1 "Rotigotine for restless legs syndrome". Drugs of Today 45 (9): 663–668. September 2009. doi:10.1358/dot.2009.45.9.1399952. PMID 19956807. 
  4. "Antidepressant properties of rotigotine in experimental models of depression". European Journal of Pharmacology 548 (1–3): 106–114. October 2006. doi:10.1016/j.ejphar.2006.07.022. PMID 16959244. 
  5. "Synthesis and radioreceptor binding activity of N-0437, a new, extremely potent and selective D2 dopamine receptor agonist". Pharmaceutisch Weekblad. Scientific Edition 7 (5): 208–211. October 1985. doi:10.1007/bf02307578. PMID 2933633. 
  6. Development & Commercialization of rotigotine by Aderis (Aderis Pharmaceuticals making a reference for the commercialization of rotigotine)
  7. "SCHWARZ PHARMA ACQUIRES REMAINING RIGHTS TO ROTIGOTINE FROM ADERIS | FDAnews". https://www.fdanews.com/articles/74339-schwarz-pharma-acquires-remaining-rights-to-rotigotine-from-aderis. 
  8. PubChem. "Rotigotine". https://pubchem.ncbi.nlm.nih.gov/compound/59227. 
  9. "Rotigotine transdermal patch in Parkinson's disease: a systematic review and meta-analysis". PLOS ONE 8 (7): e69738. 23 July 2013. doi:10.1371/journal.pone.0069738. PMID 23936090. Bibcode2013PLoSO...869738Z. 
  10. "Neupro Patch Re-launches in the US". http://www.pdf.org/en/media_pr/release/pr_1342559027. 
  11. "Tolerability and safety of ropinirole versus other dopamine agonists and levodopa in the treatment of Parkinson's disease: meta-analysis of randomized controlled trials". Drug Safety 33 (2): 147–161. February 2010. doi:10.2165/11319860-000000000-00000. PMID 20082541. 
  12. 12.0 12.1 Parkinson Study Group (December 2003). "A controlled trial of rotigotine monotherapy in early Parkinson's disease". Archives of Neurology 60 (12): 1721–1728. doi:10.1001/archneur.60.12.1721. PMID 14676046. 
  13. "Impulse control disorders arising in 3 patients treated with rotigotine". Clinical Neuropharmacology 32 (2): 59–62. 2009. doi:10.1097/WNF.0B013E3181684542. PMID 18978496. 
  14. 14.0 14.1 14.2 14.3 "Rotigotine is a potent agonist at dopamine D1 receptors as well as at dopamine D2 and D3 receptors". British Journal of Pharmacology 172 (4): 1124–1135. February 2015. doi:10.1111/bph.12988. PMID 25339241. 
  15. 15.0 15.1 "The in vitro receptor profile of rotigotine: a new agent for the treatment of Parkinson's disease". Naunyn-Schmiedeberg's Archives of Pharmacology 379 (1): 73–86. January 2009. doi:10.1007/s00210-008-0341-4. PMID 18704368. 

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