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.

Dopamine receptor D<sub>4</sub> Protein-coding gene in the species Homo sapiens

The dopamine receptor D4 is a dopamine D2-like G protein-coupled receptor encoded by the DRD4 gene on chromosome 11 at 11p15.5.

<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). In PD the dose needs to be adjusted to the effect and treatment should not be suddenly stopped. It is taken by mouth.

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

Raclopride is a typical antipsychotic. It acts as a selective antagonist on D2 dopamine receptors. It has been used in trials studying Parkinson Disease.

<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 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(DA) 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 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. The use of dopamine agonists is associated with impulse control disorders and dopamine agonist withdrawal syndrome (DAWS).

<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 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">CY-208,243</span> Chemical compound

CY-208,243 is a drug which acts as a dopamine agonist selective for the D1 subtype. Unlike most D1-selective agonists, it shows efficacy in animal models of Parkinson's disease.

<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.

References

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