Tolcapone

3,4-dihydroxy -4 '- methyl-5- nitrobenzophenone

N04BX01

COMT inhibitors

144-145 ° C

Attention

> 2000 mg · kg -1 ( LD50, rat, oral)

Template: Infobox chemical / molecular formula search available

Tolcapone is the international non-proprietary name (INN ) of the active ingredient for the treatment of Parkinson 's disease. Chemically, the active compound is a substituted benzophenone. Tolcapone was recognized in 1998 by the PZ Innovation Award.

Representation

The starting compound is a benzyl -protected aromatic aldehyde. This is reacted with butyllithium and 4- bromotoluene. The secondary alcohol thus obtained is then first oxidized with PCC, and then removed the benzyl group with hydrobromic acid. Nitration with nitric acid and methyl ether cleavage with hydrobromic acid gives the tolcapone.

Operation

Cause of Parkinson's disease is the destruction of dopaminergic cells of the substantia nigra, which triggers a dopamine deficiency and thus a predominantly cholinergic and glutaminergenen excitation mechanism in the basal ganglia. To administer the drug as a lack of dopamine will not lead to the destination, because it can not cross the blood- brain barrier. However, this is possible with the dopamine precursor ( prodrug ) of L- dopa ( dihydroxyphenylalanine ) for which there is an active transporters at the blood -brain barrier. L -dopa is rapidly metabolized 3-O -methyldopa (3- OMD), however by the enzymatic reaction of catechol -O- methyltransferase ( COMT).

This is where the effect of tolcapone; it inhibits ( " inhibited " ) the COMT enzyme and is the first compound for which this effect was observed. Thus it helps, as well as other therapeutic approaches, the balance of disturbed in PD patients neurotransmission restore. Tolcapone prevents the breakdown of L-dopa is not only circumferentially, but also the center, as it can cross the blood- brain barrier. Characterized the half-life of L-dopa in the plasma is quadrupled. This has the result that the bioavailability of dopamine in the central nervous system (CNS) and increase its concentration in the brain but not in the peripheral plasma levels. The combination with L -dopa as co-medication reduces motor fluctuations significantly. At an early stage of the disease the complication-free time, in combination with L -dopa and a decarboxylase inhibitor, significantly prolonged. While efforts are being discussed and central effects, but their clinical relevance to this day are unclear.

Side effects

Most often, the following undesirable effects include: dyskinesia ( involuntary movements ), dry mouth, nausea, vomiting, abdominal pain, insomnia, increased sweating, decreased appetite, diarrhea, fainting, headache, dizziness on standing, constipation, chest pain, respiratory infection, sleepiness, confusion and hallucinations. Liver dysfunction, in individual cases has been observed severe hepatitis.

Admission

In 1997, tolcapone was approved by the Hoffmann- La Roche as Tasmar Europe for the treatment of Parkinson's disease. Only a year later ordered the European Medicines Agency, a suspension of admission, after serious hepatotoxic side effects were encountered. Since 2004 Tasmar ( pharmaceutical company Meda AB) is, however, permitted again under strict conditions (liver function test ), the application is the adjunctive treatment of Parkinson's disease in combination with L-Dopa/Benserazid or L-DOPA/carbidopa.

* ULN = upper limit of normal ( ULN )

Trade names

• Tasmar