Tolcapone, sold under the brand name Tasmar, is a medication used to treat Parkinsons disease (PD). It is a selective, potent and reversible nitrocatechol-type inhibitor of the enzyme catechol-O-methyltransferase (COMT). It has demonstrated significant liver toxicity, which has led to suspension of marketing authorisations in a number of countries. In comparison with entacapone, another nitrocatechol COMT inhibitor, tolcapone has a longer half life (2.9 hours vs. 0.8 hours) and can better penetrate the blood–brain barrier, acting both in the central nervous system and in the periphery. However, entacapone is less toxic for the liver. Medical uses
Tolcapone is used in the treatment of Parkinsons disease as an adjunct to levodopa/carbidopa or levodopa/benserazide medications. Levodopa is a prodrug for dopamine, which reduces Parkinson symptoms; carbidopa and benserazide are aromatic L-amino acid decarboxylase (AADC) inhibitors.Without administration of tolcapone, the beneficial effects of levodopa tend to wear off more quickly, resulting in motor fluctuations. Contraindications
Combining tolcapone with non-selective monoamine oxidase inhibitors such as phenelzine or tranylcypromine is contraindicated. Tolcapone is also contraindicated for people with liver diseases or increased liver enzymes. Side effects
Tolcapone has demonstrated significant liver toxicity (hepatotoxicity) that limits the drugs utility. Entacapone is an alternative, largely since it has a more favorable toxicity profile. The hepatotoxicity can be related to elevated levels of transaminases, but studies have shown that minimal risk exists for those without preexisting liver conditions when their enzyme levels were being monitored.
Its chemical name is 3,4-dihydroxy-4-methyl-5-nitrobenzophenone. Synthesis
A synthesis of tolcapone proposed in 2008, begins with a Grignard reaction between a benzaldehyde derivative and p-tolyl magnesium bromide. The alcohol thus produced is then converted to a ketone using sodium t-butoxide. The benzyl protecting group is removed by palladium-catalyzed hydrogenation in the presence of ammonium formate. A nitro group is introduced at the 5-position adjacent to the hydroxyl group unmasked in the cleavage of the benzyl ether. The synthesis ends with cleavage of the methoxy group using aluminum chloride to yield the product alcohol. History
Tolcapone was introduced into the European market in August 1997, and subsequently into the United States market in March 1998. Liver toxicity was reported in four people who were administered tolcapone, three people died due to complications. Consequentially, the marketing authorization of tolcapone was suspended from December, 1998 until August, 2004 when it was lifted. In November 1998, the company that manufactured tolcapone voluntarily  removed the drug from the market. The authorization was then renewed in August 2009.As a result of reported complications, the U.S. Food and Drug Administration (FDA) issued a black box warning for tolcapone and label revisions that aimed to regulate the monitoring of those prescribed tolcapone for Parkinsons disease in November 1998. A number of other countries withdrew tolcapone from the market; Australia in February 1999, Bulgaria in April 1999, Iceland in November 1998, Lithuania in December 1998.