Parkinson's disease (PD) is a
neurological disorder characterized by the degeneration of dopaminergic neurons, with consequent reduction in striatal
dopamine levels leading to characteristic motor symptoms. The most effective treatment for this disease continues to be the
dopamine replacement
therapy with
levodopa together with an inhibitor of
aromatic amino acid decarboxylase (AADC). The efficacy of this
therapy, however, decreases with time and most patients develop fluctuating responses and
dyskinesias. The last decade showed that the use of
catechol-O-methyltransferase inhibitors as adjuvants to the
levodopa/AADC inhibitor
therapy, significantly improves the clinical benefits of this
therapy. The purpose of this article is to review the current knowledge on the
enzyme catechol-O-methyltransferase (COMT) and the role of COMT inhibitors in PD as a new therapeutic approach to PD involving conversion of
levodopa to
dopamine at the target region in the brain and facilitation of the continuous action of this
amine at the receptor sites. A historical overview of the discovery and development of COMT inhibitors is presented with a special emphasis on
nebicapone, presently under clinical development, as well as
entacapone and
tolcapone, which are already approved as adjuncts in the
therapy of PD. This article reviews human pharmacokinetic and pharmacodynamic properties of these drugs as well as their clinical efficacy and safety.