Catechol-O-methyltransferase inhibition by U-0521 increases striatal utilization of levodopa.

The effects of U-0521, a catechol-O-methyltransferase (COMT) inhibitor, were studied on this enzyme activity and on Dopa metabolism in rat striatum. In vivo maximal inhibition (95%) of COMT activity was obtained at 5 min with enzyme recovery to 64% of basal activity at 120 min. When injected in increasing doses U-0521 (200 mg . kg-1) inhibited, at 10 min, COMT activity by 85% with an IC50 = 80 mg . kg-1. In rats pretreated with U-0521 and then with DOPA the accumulation of 3-O-methyldopa-(OMD) in the plasma was essentially blocked while Dopa, dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) accumulation in the striatum was significantly higher than in DOPA treated controls. U-0521, a potent COMT inhibitor, enhances the availability and utilization of levodopa in the brain and may thus be helpful in future treatment of parkinsonian patients.