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Rotigotine
Clinical data
Trade names	Neupro, Leganto
AHFS/Drugs.com	Monograph
MedlinePlus	a607059
License data	US DailyMed: Rotigotine;
Pregnancy; category	AU: B3; ;
Routes of; administration	Transdermal patch
ATC code	N04BC09 (WHO) ;
Legal status
Legal status	AU: S4 (Prescription only); BR: Class C1 (Other controlled substances); US: ℞-only; EU: Rx-only; In general: ℞ (Prescription only);
Pharmacokinetic data
Bioavailability	37% (transdermal)
Protein binding	92%
Metabolism	Liver (CYP-mediated)
Elimination half-life	5–7 hours
Excretion	Urine (71%), Feces (23%)
Identifiers
	IUPAC name (S)-6-[Propyl(2-thiophen-2-ylethyl)amino]-5,6,7,8- tetrahydronaphthalen-1-ol;
CAS Number	99755-59-6 ;
PubChem CID	57537;
IUPHAR/BPS	941;
DrugBank	DB05271 ;
ChemSpider	51867 ;
UNII	87T4T8BO2E;
KEGG	D05768;
ChEMBL	ChEMBL1303 ;
CompTox Dashboard (EPA)	DTXSID5046772 ;
ECHA InfoCard	100.123.257
Chemical and physical data
Formula	C19H25NOS
Molar mass	315.48 g·mol−1
3D model (JSmol)	Interactive image;
	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 ; Key:KFQYTPMOWPVWEJ-UHFFFAOYSA-N ;
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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.^[3]^[4] 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.^[3]

Like other dopamine agonists, rotigotine has been shown to possess antidepressant effects and may be useful in the treatment of depression as well.^[5]

History

Initially developed at the University of Groningen in 1985 as N-0437,^[6] 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,^[7] which firm was acquired by UCB S.A. in 2006. Schwarz completed acquisition of full rights to rotigotine from Aderis as of 2005.^[8]

The drug was approved by the European Medicines Agency (EMA) for use in Europe in 2006.^[2] In 2007, the Neupro patch was approved by the Food and Drug Administration (FDA).^[9] 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.^[10] The patch was reformulated, and was reintroduced in the United States in 2012.^[11]

Rotigotine was authorized as a treatment for restless-legs syndrome in August 2008.^[4]

Side effects

General side effects for rotigotine may include constipation, dyskinesia, nausea, vomiting, dizziness, fatigue, insomnia, somnolence, confusion, and hallucinations.^[12]^[13] More serious complications can include psychosis and impulse control disorders like hypersexuality, punding, and pathological gambling.^[14] Mild adverse skin reactions at the patch application site may also occur.^[3]^[13]

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.^[15] 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.^[15] In functional studies however, rotigotine behaves as a full agonist of D₁, D₂, and D₃ with similar potencies (EC₅₀).^[15] 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.^[15]

*In vitro* receptor binding profile of rotigotine^[16]
Receptor	K_i (nM)
D₁	83
D₂	13.5
D₃	0.71
D_4.2	3.9
D_4.4	15
D_4.7	5.9
D₅	5.4
α_1A	176
α_1B	273
α_2A	338
α_2B	27
α_2C	135
5-HT_1A	30
5-HT₇	86
H₁	330

All affinities listed were assayed using human materials except that for α_2B-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 α_2B-adrenergic receptor, and as a partial agonist at the 5-HT_1A receptor.^[16] 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 α_2B-adrenergic and 5-HT_1A activity also possibly having some minor relevance.

References

^ 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.
^ ^a ^b "Neupro EPAR". European Medicines Agency. 17 September 2018. Retrieved 2 March 2020.
^ ^a ^b ^c 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.
^ ^a ^b 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.
^ 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.
^ 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.
^ Development & Commercialization of rotigotine by Aderis (Aderis Pharmaceuticals making a reference for the commercialization of rotigotine)
^ "SCHWARZ PHARMA ACQUIRES REMAINING RIGHTS TO ROTIGOTINE FROM ADERIS | FDAnews". www.fdanews.com. Retrieved 11 August 2022.
^ PubChem. "Rotigotine". pubchem.ncbi.nlm.nih.gov. Retrieved 11 August 2022.
^ 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.
^ "Neupro Patch Re-launches in the US". Archived from the original on 23 March 2016. Retrieved 12 September 2012.
^ 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.
^ ^a ^b 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.
^ 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.
^ ^a ^b ^c ^d 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.
^ ^a ^b 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.