Rotigotine

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.[1][2] 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.[1]

Rotigotine
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)
  • US: ℞-only
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability37% (transdermal)
Protein binding92%
MetabolismHepatic (CYP-mediated)
Elimination half-life5–7 hours
ExcretionUrine (71%), Fecal (23%)
Identifiers
IUPAC name
  • (S)-6-[Propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8- tetrahydronaphthalen-1-ol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.123.257
Chemical and physical data
FormulaC19H25NOS
Molar mass315.48 g·mol−1
3D model (JSmol)
SMILES
  • Oc1cccc3c1CCC(N(CCC)CCc2sccc2)C3
InChI
  • InChI=1S/C19H25NOS/c1-2-11-20(12-10-17-6-4-13-22-17)16-8-9-18-15(14-16)5-3-7-19(18)21/h3-7,13,16,21H,2,8-12,14H2,1H3 Y
  • Key:KFQYTPMOWPVWEJ-UHFFFAOYSA-N Y
 NY (what is this?)  (verify)

Like other dopamine agonists, rotigotine has been shown to possess antidepressant effects and may be useful in the treatment of depression as well.[3]

History

Initially developed at the University of Groningen in 1985 as N-0437,[4] Aderis Pharmaceuticals acquired rotigotine and continued development toward commercialization. In 1998, Aderis globally out-licensed rotigotine for development and commercialization to Schwarz Pharma,[5] which firm was acquired by UCB S.A. in 2006. Schwarz completed acquisition of full rights to rotigotine from Aderis as of 2005.[6]

The drug was approved by the European Medicines Agency (EMA) for use in Europe in 2006.[7] 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. 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.[2]

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.[1][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]

Rotigotine possesses the following in vitro receptor binding profile:[15]

  • D1 receptor (Ki = 83 nM)
  • D2 receptor (Ki = 13.5 nM)
  • D3 receptor (Ki = 0.71 nM)
  • D4.2 receptor (Ki = 3.9 nM)
  • D4.4 receptor (Ki = 15 nM)
  • D4.7 receptor (Ki = 5.9 nM)
  • D5 receptor (Ki = 5.4 nM)
  • α1A-adrenergic receptor (Ki = 176 nM)
  • α1B-adrenergic receptor (Ki = 273 nM)
  • α2A-adrenergic receptor (Ki = 338 nM)
  • α2B-adrenergic receptor (Ki = 27 nM)
  • α2C-adrenergic receptor (Ki = 135 nM)
  • 5-HT1A receptor (Ki = 30 nM)
  • 5-HT7 receptor (Ki = 86 nM)
  • H1 receptor (Ki = 330 nM)

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.

See also

References
  1. Chen JJ, Swope DM, Dashtipour K, Lyons KE (December 2009). "Transdermal rotigotine: a clinically innovative dopamine-receptor agonist for the management of Parkinson's disease". Pharmacotherapy. 29 (12): 1452–1467. doi:10.1592/phco.29.12.1452. PMID 19947805. S2CID 40466260.
  2. Davies S (September 2009). "Rotigotine for restless legs syndrome". Drugs of Today. 45 (9): 663–668. doi:10.1358/dot.2009.45.9.1399952. PMID 19956807.
  3. Bertaina-Anglade V, La Rochelle CD, Scheller DK (October 2006). "Antidepressant properties of rotigotine in experimental models of depression". European Journal of Pharmacology. 548 (1–3): 106–114. doi:10.1016/j.ejphar.2006.07.022. PMID 16959244.
  4. Horn AS, Tepper P, Van der Weide J, Watanabe M, Grigoriadis D, Seeman P (October 1985). "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. doi:10.1007/bf02307578. PMID 2933633. S2CID 8847550.
  5. Development & Commercialization of rotigotine by Aderis (Aderis Pharmaceuticals making a reference for the commercialization of rotigotine)
  6. "SCHWARZ PHARMA ACQUIRES REMAINING RIGHTS TO ROTIGOTINE FROM ADERIS | FDAnews". www.fdanews.com. Retrieved 11 August 2022.
  7. "Neupro EPAR". European Medicines Agency. 17 September 2018. Retrieved 2 March 2020.
  8. PubChem. "Rotigotine". pubchem.ncbi.nlm.nih.gov. Retrieved 11 August 2022.
  9. Zhou CQ, Li SS, Chen ZM, Li FQ, Lei P, Peng GG (23 July 2013). "Rotigotine transdermal patch in Parkinson's disease: a systematic review and meta-analysis". PLOS ONE. 8 (7): e69738. Bibcode:2013PLoSO...869738Z. doi:10.1371/journal.pone.0069738. PMC 3720658. PMID 23936090.
  10. Neupro Patch Re-launches in the US
  11. Kulisevsky J, Pagonabarraga J (February 2010). "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. doi:10.2165/11319860-000000000-00000. PMID 20082541. S2CID 34876593.
  12. 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. Wingo TS, Evatt M, Scott B, Freeman A, Stacy M (2009). "Impulse control disorders arising in 3 patients treated with rotigotine". Clinical Neuropharmacology. 32 (2): 59–62. doi:10.1097/WNF.0B013E3181684542. PMID 18978496. S2CID 23942499.
  14. Wood M, Dubois V, Scheller D, Gillard M (February 2015). "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. doi:10.1111/bph.12988. PMC 4314200. PMID 25339241.
  15. Scheller D, Ullmer C, Berkels R, Gwarek M, Lübbert H (January 2009). "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. doi:10.1007/s00210-008-0341-4. PMID 18704368. S2CID 25112443.
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