A series of new and selective catechol-O-methyltransferase (COMT) inhibitors have been developed. Entacapone, nitecapone and tolcapone are nitrocatechol-type agents that are potent COMT inhibitorsin vitroand are activein vivoafter oral administration. CGP 28014 is a pyridine derivative that is active onlyin vivo.In animal studies, these compounds inhibit effectively theO-methylation of levodopa, thus improving its bioavailability and brain penetration, and potentiating its behavioural effects. Entacapone and nitecapone have mainly peripheral effects, whereas tolcapone and CGP 28014 inhibitO-methylation also in the brain. In human volunteers, entacapone, nitecapone and tolcapone inhibit dose-dependently COMT activity of erythrocytes. COMT inhibitors also decrease the levels of COMT-dependent metabolites of adrenaline (epinephrine) and noradrenaline (norepinephrine) in plasma.Entacapone, tolcapone and CGP 28014 improve the bioavailability of levodopa and inhibit the formation of 3-O-methyldopa in human volunteers. In initial clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiated and prolonged the therapeutic effects of levodopa.