Rotigotine

Rotigotine (Neupro) 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.

History
Rotigotine was developed by Aderis Pharmaceuticals. 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.

Chemistry
Rotigotine is analogous to 7-OH-DPAT 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.

Pharmacology
Rotigotine possesses the following in vitro receptor binding 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 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. 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.

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