Rotigotine
Encyclopedia
Rotigotine is a non-ergoline
dopamine agonist
indicated for the treatment of Parkinson's disease
(PD) and restless legs syndrome
(RLS) in Europe
and the United States
. 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.
Like other dopamine agonists, rotigotine has been shown to possess antidepressant
effects and may be useful in the treatment of depression as well.
. In 1998, Aderis licensed worldwide development and commercialization rights for rotigotine to the German
pharmaceutical company
Schwarz Pharma (today a subsidiary of the Belgian
company UCB S.A.
).
The drug has been approved by the EMEA
for use in Europe in 2006 and is today being sold in several European countries. In 2007, the Neupro patch was approved by the Food and Drug Administration
(FDA) as the first transdermal treatment of Parkinson's disease in the United States
. However, as of 2008, Schwarz Pharma has recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism.
Rotigotine has been authorized as a treatment for RLS since August 2008.
and UH-232
, all three of which are aminotetralin derivatives. These compounds are similar in structure
to dopamine
, likely underlying their pharmacology
.
Cusack, N. J.; Peck, J. V.; Drugs Future 1993, 18, 1005.
receptor
binding
profile:
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. Though it has affinity for a large number of sites as shown above, at clinical doses rotigotine behaves mostly as a selective
D2-like (D2, D3, D4) and D5 receptor agonist, with its α2B-adrenergic and 5-HT1A activity also possibly having some low relevance.
s for rotigotine may include constipation
, dyskinesia
, nausea
, vomiting
, dizziness
, fatigue, insomnia
, somnolence
, confusion
, and hallucination
s. More serious complications can include psychosis
and impulse control disorder
s like hypersexuality
, punding, and pathological gambling. Mild adverse skin reactions at the patch application site may also occur.
Ergoline
Ergoline is a chemical compound whose structural skeleton is contained in a diverse range of alkaloids including a few psychedelic drugs . Ergoline derivatives are used clinically for the purpose of vasoconstriction and in the treatment of migraines and Parkinson's disease...
dopamine agonist
Dopamine agonist
A dopamine agonist is a compound that activates dopamine receptors in the absence of dopamine. Dopamine agonists activate signaling pathways through the dopamine receptor and trimeric G-proteins, ultimately leading to changes in gene transcription.-Uses:...
indicated for the treatment of Parkinson's disease
Parkinson's disease
Parkinson's disease is a degenerative disorder of the central nervous system...
(PD) and restless legs syndrome
Restless legs syndrome
Restless legs syndrome or Willis-Ekbom disease is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs, but can affect the arms, torso, and even phantom limbs...
(RLS) in Europe
Europe
Europe is, by convention, one of the world's seven continents. Comprising the westernmost peninsula of Eurasia, Europe is generally 'divided' from Asia to its east by the watershed divides of the Ural and Caucasus Mountains, the Ural River, the Caspian and Black Seas, and the waterways connecting...
and the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. It is formulated as a once-daily transdermal patch
Transdermal patch
A transdermal patch is a medicated adhesive patch that is placed on the skin to deliver a specific dose of medication through the skin and into the bloodstream. Often, this promotes healing to an injured area of the body. An advantage of a transdermal drug delivery route over other types of...
which provides a slow and constant supply of the drug over the course of 24 hours.
Like other dopamine agonists, rotigotine has been shown to possess antidepressant
Antidepressant
An antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. According to Gelder, Mayou &*Geddes people with a depressive illness will experience a therapeutic effect to their mood;...
effects and may be useful in the treatment of depression as well.
History
Rotigotine was developed by Aderis PharmaceuticalsAderis Pharmaceuticals
Aderis Pharmaceuticals was founded in 1994 to develop and commercialize pharmaceuticals and it is best known for the development of Rotigotine a dopamine agonist made for the treatment of Parkinson's disease.- External links :* * *...
. In 1998, Aderis licensed worldwide development and commercialization rights for rotigotine to the German
Germany
Germany , officially the Federal Republic of Germany , is a federal parliamentary republic in Europe. The country consists of 16 states while the capital and largest city is Berlin. Germany covers an area of 357,021 km2 and has a largely temperate seasonal climate...
pharmaceutical company
Pharmaceutical company
The pharmaceutical industry develops, produces, and markets drugs licensed for use as medications. Pharmaceutical companies are allowed to deal in generic and/or brand medications and medical devices...
Schwarz Pharma (today a subsidiary of the Belgian
Belgium
Belgium , officially the Kingdom of Belgium, is a federal state in Western Europe. It is a founding member of the European Union and hosts the EU's headquarters, and those of several other major international organisations such as NATO.Belgium is also a member of, or affiliated to, many...
company UCB S.A.
UCB (company)
UCB is a multinational biopharmaceutical manufacturing company headquartered in Brussels, Belgium.- History :UCB was founded on 18 January 1928 by Emmanuel Janssen, a Belgian businessman...
).
The drug has been approved by the EMEA
European Medicines Agency
The European Medicines Agency is a European agency for the evaluation of medicinal products. From 1995 to 2004, the European Medicines Agency was known as European Agency for the Evaluation of Medicinal Products.Roughly parallel to the U.S...
for use in Europe in 2006 and is today being sold in several European countries. In 2007, the Neupro patch was approved by the Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...
(FDA) as the first transdermal treatment of Parkinson's disease in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
. However, as of 2008, Schwarz Pharma has recalled all Neupro patches in the United States and some in Europe because of problems with the delivery mechanism.
Rotigotine has been authorized as a treatment for RLS since August 2008.
Chemistry
Rotigotine is analogous to 7-OH-DPAT7-OH-DPAT
7-OH-DPAT is a synthetic compound that acts as a dopamine receptor agonist with reasonable selectivity for the D3 receptor subtype, and low affinity for serotonin receptors, unlike its structural isomer 8-OH-DPAT....
and UH-232
UH-232
UH-232 is a drug which acts as a subtype selective mixed agonist-antagonist for dopamine receptors, acting as a weak partial agonist at the D3 subtype, and an antagonist at D2Sh autoreceptors on dopaminergic nerve terminals. This causes dopamine release in the brain and has a stimulant effect, as...
, all three of which are aminotetralin derivatives. These compounds are similar in structure
Chemical structure
A chemical structure includes molecular geometry, electronic structure and crystal structure of molecules. Molecular geometry refers to the spatial arrangement of atoms in a molecule and the chemical bonds that hold the atoms together. Molecular geometry can range from the very simple, such as...
to dopamine
Dopamine
Dopamine is a catecholamine neurotransmitter present in a wide variety of animals, including both vertebrates and invertebrates. In the brain, this substituted phenethylamine functions as a neurotransmitter, activating the five known types of dopamine receptors—D1, D2, D3, D4, and D5—and their...
, likely underlying their pharmacology
Pharmacology
Pharmacology is the branch of medicine and biology concerned with the study of drug action. More specifically, it is the study of the interactions that occur between a living organism and chemicals that affect normal or abnormal biochemical function...
.
Cusack, N. J.; Peck, J. V.; Drugs Future 1993, 18, 1005.
Pharmacology
Rotigotine possesses the following in vitroIn vitro
In vitro refers to studies in experimental biology that are conducted using components of an organism that have been isolated from their usual biological context in order to permit a more detailed or more convenient analysis than can be done with whole organisms. Colloquially, these experiments...
receptor
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
binding
Binding (molecular)
Molecular binding is an attractive interaction between two molecules which results in a stable association in which the molecules are in close proximity to each other...
profile:
- 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 receptorAlpha-1A adrenergic receptorThe alpha-1A adrenergic receptor , also known as ADRA1A, formerly known as the alpha-1C adrenergic receptor, is an alpha-1 adrenergic receptor, and also denotes the human gene encoding it.-Agonists:...
(Ki = 176 nM) - α1B-adrenergic receptorAlpha-1B adrenergic receptorThe alpha-1B adrenergic receptor , also known as ADRA1B, is an alpha-1 adrenergic receptor, and also denotes the human gene encoding it.-Interactions:...
(Ki = 273 nM) - α2A-adrenergic receptorAlpha-2A adrenergic receptorThe alpha-2A adrenergic receptor , also known as ADRA2A, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.-Role in Central Nervous System:...
(Ki = 338 nM) - α2B-adrenergic receptorAlpha-2B adrenergic receptorThe alpha-2B adrenergic receptor , is a G-protein coupled receptor. It is a subtype of the adrenergic receptor family. The human gene encoding this receptor has the symbol ADRA2B.ADRA2B orthologs have been identified in several mammals....
(Ki = 27 nM) - α2C-adrenergic receptorAlpha-2C adrenergic receptorThe alpha-2C adrenergic receptor , also known as ADRA2C, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.-Agonists:* -3-Nitrobiphenyline -Antagonists:...
(Ki = 135 nM)
- 5-HT1A receptor5-HT1A receptorThe 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
(Ki = 30 nM) - 5-HT7 receptor5-HT7 receptorThe 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin The 5-HT7 receptor is coupled to Gs and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various...
(Ki = 86 nM) - H1 receptorH1 receptorThe H1 receptor is a histamine receptor belonging to the family of Rhodopsin like G-protein-coupled receptors. This receptor, which is activated by the biogenic amine histamine, is expressed throughout the body, to be specific, in smooth muscles, on vascular endothelial cells, in the heart, and in...
(Ki = 330 nM)
All affinities listed were assayed using human
Human
Humans are the only living species in the Homo genus...
materials except that for α2B-adrenergic which was done with NG 108–15 cells. Rotigotine behaves as a partial
Partial agonist
Partial agonists bind and activate a given receptor, but have only partial efficacy at the receptor relative to a full agonist...
or full agonist (depending on the assay) at all dopamine receptors listed, as an antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
at the α2B-adrenergic receptor, and as a partial agonist at the 5-HT1A receptor. Though it has affinity for a large number of sites as shown above, at clinical doses rotigotine behaves mostly as a selective
Binding selectivity
Binding selectivity refers to the differing affinities with which different ligands bind to a substrate forming a complex. A selectivity coefficient is the equilibrium constant for the reaction of displacement by one ligand of another ligand in a complex with the substrate...
D2-like (D2, D3, D4) and D5 receptor agonist, with its α2B-adrenergic and 5-HT1A activity also possibly having some low relevance.
Side effects
General side effectSide effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
s for rotigotine may include constipation
Constipation
Constipation refers to bowel movements that are infrequent or hard to pass. Constipation is a common cause of painful defecation...
, dyskinesia
Dyskinesia
Dyskinesia is a movement disorder which consists of effects including diminished voluntary movements and the presence of involuntary movements, similar to tics or choreia. Dyskinesia can be anything from a slight tremor of the hands to uncontrollable movement of, most commonly, the upper body but...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, vomiting
Vomiting
Vomiting is the forceful expulsion of the contents of one's stomach through the mouth and sometimes the nose...
, dizziness
Dizziness
Dizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
, fatigue, insomnia
Insomnia
Insomnia is most often defined by an individual's report of sleeping difficulties. While the term is sometimes used in sleep literature to describe a disorder demonstrated by polysomnographic evidence of disturbed sleep, insomnia is often defined as a positive response to either of two questions:...
, somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
, confusion
ConFusion
ConFusion is an annual science fiction convention organized by the Stilyagi Air Corps and its parent organization, the Ann Arbor Science Fiction Association. Commonly, it is held the third weekend of January. It is the oldest science fiction convention in Michigan, a regional, general SF con...
, and hallucination
Hallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s. More serious complications can include psychosis
Psychosis
Psychosis means abnormal condition of the mind, and is a generic psychiatric term for a mental state often described as involving a "loss of contact with reality"...
and impulse control disorder
Impulse control disorder
Impulse control disorder is a set of psychiatric disorders including intermittent explosive disorder, kleptomania, pathological gambling, pyromania , and three body-focused repetitive or compulsive behaviors of trichotillomania , onychophagia and dermatillomania...
s like hypersexuality
Hypersexuality
Hypersexuality is extremely frequent or suddenly increased sexual urges or sexual activity. Hypersexuality is typically associated with lowered sexual inhibitions. Although hypersexuality can be caused by some medical conditions or medications, in most cases the cause is unknown...
, punding, and pathological gambling. Mild adverse skin reactions at the patch application site may also occur.