Tolcapone appears to be peripherally selective, but can still cross into the brain in significant amounts and has been found to inhibit COMT centrally as well.

Levodopa is a prodrug for dopamine, which reduces Parkinson symptoms; carbidopa and benserazide are aromatic L-amino acid decarboxylase (AADC) inhibitors.

[9] Without administration of tolcapone, the beneficial effects of levodopa tend to wear off more quickly, resulting in motor fluctuations.

No clear mechanism is implicated, but it has been hypothesized that it has something to do with abnormal mitochondrial respiration due to the uncoupling of oxidative phosphorylation.

[12] Treatment with tolcapone runs the risk of eliciting or prolonging dyskinesia; this can be counteracted by decreasing the dose of levodopa.

This occurs because the administration of tolcapone results in the accumulation of the biological methyl donor S-adenosyl-L-methionine (SAM) in the striatum that induces Parkinson symptoms.

[12] Tolcapone selectively and reversibly[11] binds to the catalytic site of COMT in both the periphery and the central nervous system (CNS) with greater affinity than any of the three catecholamines, including levodopa.

Additionally, levodopa that has already reached the CNS, after being converted to dopamine, will not be degraded as quickly when tolcapone inhibits COMT activity.

[7] Tolcapone is an intensely yellow, odorless, bitter tasting, non-hygroscopic, crystalline compound with a relative molecular mass of 273.25 g/mol.

The pKa values are 4.5 and 10.6 for the two phenyl groups; and the maximum absorption is at 268 nm (in 0.1 M hydrochloric acid / ethanol).

The synthesis ends with cleavage of the methoxy group using aluminum chloride to yield the product alcohol.

[25] 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.

[27] In animal studies, tolcapone shows antidepressant- and anti-anhedonia-like effects, stimulates exploratory behavior, and enhances the locomotor hyperactivity induced by psychostimulants like amphetamine and nomifensine.

[31][32] There is also interest in brain-penetrant COMT inhibitors like tolcapone for the treatment of schizophrenia[31][33] as well as disorders of diminished motivation like apathy.