Rotigotine

Last updated

Rotigotine
Rotigotine.svg
Clinical data
Trade names Neupro, Leganto
AHFS/Drugs.com Monograph
MedlinePlus a607059
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) [1]
  • US: ℞-only
  • EU:Rx-only [2]
  • 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
  • (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 InfoCard 100.123.257 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C19H25NOS
Molar mass 315.48 g·mol−1
3D model (JSmol)
  • Oc1cccc3c1CCC(N(CCC)CCc2sccc2)C3
  • 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 Yes check.svgY
  • Key:KFQYTPMOWPVWEJ-UHFFFAOYSA-N Yes check.svgY
 X mark.svgNYes check.svgY  (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. [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]

Contents

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]
ReceptorKi (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. [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 α2B-adrenergic and 5-HT1A activity also possibly having some minor relevance.

Related Research Articles

<span class="mw-page-title-main">Dopamine receptor</span> Class of G protein-coupled receptors

Dopamine receptors are a class of G protein-coupled receptors that are prominent in the vertebrate central nervous system (CNS). Dopamine receptors activate different effectors through not only G-protein coupling, but also signaling through different protein interactions. The neurotransmitter dopamine is the primary endogenous ligand for dopamine receptors.

<span class="mw-page-title-main">Dopamine antagonist</span> Drug which blocks dopamine receptors

A dopamine antagonist, also known as an anti-dopaminergic and a dopamine receptor antagonist (DRA), is a type of drug which blocks dopamine receptors by receptor antagonism. Most antipsychotics are dopamine antagonists, and as such they have found use in treating schizophrenia, bipolar disorder, and stimulant psychosis. Several other dopamine antagonists are antiemetics used in the treatment of nausea and vomiting.

<span class="mw-page-title-main">Dopaminergic</span> Substance related to dopamine functions

Dopaminergic means "related to dopamine", a common neurotransmitter. Dopaminergic substances or actions increase dopamine-related activity in the brain.

<span class="mw-page-title-main">Ropinirole</span> Dopamine agonist medication

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

<span class="mw-page-title-main">Dihydrexidine</span> Chemical compound

Dihydrexidine (DAR-0100) is a moderately selective full agonist at the dopamine D1 and D5 receptors. It has approximately 10-fold selectivity for D1 and D5 over the D2 receptor. Although dihydrexidine has some affinity for the D2 receptor, it has functionally selective (highly biased) D2 signaling, thereby explaining why it lacks D2 agonist behavioral qualities.

<span class="mw-page-title-main">Pramipexole</span> Dopamine agonist medication

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

<span class="mw-page-title-main">Dopamine agonist</span> Compound that activates dopamine receptors

A dopamine agonist is a compound that activates dopamine receptors. There are two families of dopamine receptors, D1-like and D2-like. They are all G protein-coupled receptors. D1- and D5-receptors belong to the D1-like family and the D2-like family includes D2, D3 and D4 receptors. Dopamine agonists are primarily used in the treatment of the motor symptoms of Parkinson's disease, and to a lesser extent, in hyperprolactinemia and restless legs syndrome. They are also used off-label in the treatment of clinical depression. Impulse control disorders are associated with the use of dopamine agonists for whatever condition.

<span class="mw-page-title-main">Lisuride</span> Chemical compound

Lisuride, sold under the brand name Dopergin among others, is a monoaminergic medication of the ergoline class which is used in the treatment of Parkinson's disease, migraine, and high prolactin levels. It is taken by mouth.

<span class="mw-page-title-main">Piribedil</span> Drug used in the management of Parkinsons disease

Piribedil (trade names Pronoran, Trivastal Retard, Trastal, Trivastan, Clarium and others) is an antiparkinsonian agent and piperazine derivative which acts as a D2 and D3 receptor agonist. It also has α2-adrenergic antagonist properties.

<span class="mw-page-title-main">Dihydroergocryptine</span> Chemical compound

Dihydroergocryptine (DHEC), sold under the brand names Almirid and Cripar among others, is a dopamine agonist of the ergoline group that is used as an antiparkinson agent in the treatment of Parkinson's disease. It is taken by mouth.

Dopamine receptor D<sub>2</sub> Main receptor for most antipsychotic drugs

Dopamine receptor D2, also known as D2R, is a protein that, in humans, is encoded by the DRD2 gene. After work from Paul Greengard's lab had suggested that dopamine receptors were the site of action of antipsychotic drugs, several groups, including those of Solomon H. Snyder and Philip Seeman used a radiolabeled antipsychotic drug to identify what is now known as the dopamine D2 receptor. The dopamine D2 receptor is the main receptor for most antipsychotic drugs. The structure of DRD2 in complex with the atypical antipsychotic risperidone has been determined.

Dopamine receptor D<sub>1</sub> Protein-coding gene in humans

Dopamine receptor D1, also known as DRD1. It is one of the two types of D1-like receptor family — receptors D1 and D5. It is a protein that in humans is encoded by the DRD1 gene.

Dopamine receptor D<sub>5</sub> Protein-coding gene in humans

Dopamine receptor D5, also known as D1BR, is a protein that in humans is encoded by the DRD5 gene. It belongs to the D1-like receptor family along with the D1 receptor subtype.

Dopamine receptor D<sub>3</sub> Subtype of Dopamine Receptor

Dopamine receptor D3 is a protein that in humans is encoded by the DRD3 gene.

<span class="mw-page-title-main">Pardoprunox</span> Antiparkinsonian compound researched for the treatment of depression and anxiety disorders

Pardoprunox (INN) is an antiparkinsonian drug developed by Solvay for the treatment of Parkinson's disease that reached phase III clinical trials before being discontinued. It was also being investigated for the treatment of depression and anxiety but these indications appear to have been abandoned as well.

<span class="mw-page-title-main">Roxindole</span> Dopaminergic & serotonergic drug developed for schizophrenia treatment

Roxindole (EMD-49,980) is a dopaminergic and serotonergic drug which was originally developed by Merck KGaA for the treatment of schizophrenia. In clinical trials its antipsychotic efficacy was only modest but it was unexpectedly found to produce potent and rapid antidepressant and anxiolytic effects. As a result, roxindole was further researched for the treatment of depression instead. It has also been investigated as a therapy for Parkinson's disease and prolactinoma.

<span class="mw-page-title-main">Sumanirole</span> Chemical compound

Sumanirole (PNU-95,666) is a highly selective D2 receptor full agonist, the first of its kind to be discovered. It was developed for the treatment of Parkinson's disease and restless leg syndrome. While it has never been approved for medical use it is a highly valuable tool compound for basic research to identify neurobiological mechanisms that are based on a dopamine D2-linked (vs. D1-, D3-, D4-, and D5-linked) mechanism of action.

<span class="mw-page-title-main">Clorotepine</span> Antipsychotic medication

Clorotepine, also known as octoclothepin or octoclothepine, is an antipsychotic of the tricyclic group which was derived from perathiepin in 1965 and marketed in the Czech Republic by Spofa in or around 1971 for the treatment of schizophrenic psychosis.

Peripherally selective drugs have their primary mechanism of action outside of the central nervous system (CNS), usually because they are excluded from the CNS by the blood–brain barrier. By being excluded from the CNS, drugs may act on the rest of the body without producing side-effects related to their effects on the brain or spinal cord. For example, most opioids cause sedation when given at a sufficiently high dose, but peripherally selective opioids can act on the rest of the body without entering the brain and are less likely to cause sedation. These peripherally selective opioids can be used as antidiarrheals, for instance loperamide (Imodium).

<span class="mw-page-title-main">Tavapadon</span> Chemical compound

Tavapadon is a dopamine receptor agonist which is under development for the treatment of Parkinson's disease. It is under development by Cerevel Therapeutics, which acquired tavapadon from Pfizer in 2018. It is taken by mouth.

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 "Neupro EPAR". European Medicines Agency. 17 September 2018. Retrieved 2 March 2020.
  3. 1 2 3 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.
  4. 1 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.
  5. ↑ 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.
  6. ↑ 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.
  7. ↑ Development & Commercialization of rotigotine by Aderis (Aderis Pharmaceuticals making a reference for the commercialization of rotigotine)
  8. ↑ "SCHWARZ PHARMA ACQUIRES REMAINING RIGHTS TO ROTIGOTINE FROM ADERIS | FDAnews". www.fdanews.com. Retrieved 11 August 2022.
  9. ↑ PubChem. "Rotigotine". pubchem.ncbi.nlm.nih.gov. Retrieved 11 August 2022.
  10. ↑ 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.
  11. ↑ "Neupro Patch Re-launches in the US". Archived from the original on 23 March 2016. Retrieved 12 September 2012.
  12. ↑ 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.
  13. 1 2 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.
  14. ↑ 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.
  15. 1 2 3 4 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.
  16. 1 2 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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