Since its demonstration of effectiveness against Parkinson disease in 1961, levodopa has become the mainstay therapy for this disease. However, most of the orally-administered levodopa is converted by catechol-O-methyltransferase into the inactive metabolite 3-O-methyldopa before crossing the blood-brain barrier. The accumulated 3-O-methyldopa then competes with levodopa for the saturable neutral amino acid active transport system in the gut and the blood vessel wall leading to motor fluctuations. The object of catechol-O-methyltransferase inhibitors such as entacapone and tolcapone is to inhibit the action of this enzyme.
Catechol-O-methyltransferase was found to be widely distributed in human tissues such as the glia (Guldberg and Marsden 1975). Catechol-O-methyltransferase inhibition was subsequently shown to lower the circulating levels of 3-O-methyldopa and improve the bioavailability of levodopa. The first generation nonselective catechol-O-methyltransferase inhibiting drugs were studied but abandoned in the 1970s because of toxicity and lack of efficacy. The second generation catechol-O-methyltransferase inhibitors, which were developed in the late 1980s, include entacapone and tolcapone. Both of these are reversible catechol-O-methyltransferase inhibitors and are in clinical trials. Both compounds have also been approved. Entacapone acts mainly peripherally, whereas tolcapone acts both peripherally and centrally. Entacapone was approved in the European Union in 1998 and by the United States Food and Drug Administration in October 1999. A levodopa/carbidopa/entacapone combination product (Stalevo) was approved in 2003 to treat patients with idiopathic Parkinson disease who experience end-of-dose "wearing-off" (Hauser 2004).