GENERAL-PROPERTIES AND CLINICAL POSSIBILITIES OF NEW SELECTIVE INHIBITORS OF CATECHOL O-METHYLTRANSFERASE

1. The structure of catechol O-methyltransferase (COMT) has been recen tly characterized and a series of new and selective COMT inhibitors de veloped. 2. Entacapone, nitecapone and tolcapone are nitrocatechol-typ e potent COMT inhibitors in vitro (K-i in nanomolar range). They are a lso very selective for COMT and active in vivo even after oral adminis tration. CGP 28014 is a pyridine derivative that is active only in viv o. 3. In animal studies, these compounds inhibit effectively the O-met hylation of L-dopa, thus improving its bioavailability and brain penet ration and potentiating its behavioural effects. 4. Entacapone and nit ecapone have mainly a peripheral effect whereas tolcapone and CGP 2801 4 also inhibit O-methylation in the brain. 5. In man, entacapone, nite capone and tolcapone all inhibit dose dependently the COMT activity in erythrocytes. These COMT inhibitors also decrease the amount of COMT dependent metabolites of adrenaline and noradrenaline in plasma. 6. In human volunteers, entacapone, tolcapone and CGP 28014 improve the bio availability of L-dopa and inhibit the formation of 3-O-methyldopa. 7. In the first clinical studies in patients with Parkinson's disease, b oth entacapone and tolcapone potentiate and prolong the therapeutic ef fect of L-dopa.