Ralph Paulini, C. Lerner, R. Jakob‐Roetne
Sep 6, 2004
Citations
0
Influential Citations
30
Citations
Journal
ChemBioChem
Abstract
Catechol O-methyltransferase (COMT) catalyzes the O-methylation of catechols by S-adenosylmethionine (SAM) in the presence of Mg ions. Inhibition of COMT offers a therapeutic handle to reduce catecholamine metabolism, therefore providing a valuable complement for the treatment of CNS (central nervous system) disorders, such as Parkinson’s disease and possibly schizophrenia. The most efficacious therapy for Parkinson’s disease uses l-Dopa. The introduction of COMT-inhibitors (tolcapone (Tasmar8) and entacapone (Comtan8)) as adjuncts to this treatment has resulted in considerable therapeutic improvement, helping to substantially prolong the efficacy of l-Dopa dosage by preventing its catabolism through O-methylation. On the other hand, in some cases, adverse effects of hepatotoxicity have been associated with the use of tolcapone. It has been hypothesized that the hepatotoxic effect may be related to the nitrocatechol core structure of the drug. Therefore, the preparation of COMT inhibitors lacking the nitro group might be of advantage. However, this group is regarded as a key element for tight and reversible binding to the substrate pocket in the active site. Substitution of the nitro group by weaker electron-withdrawing substituents drastically reduces the affinity of catechols to COMT. Furthermore, the electron-withdrawing effect of the nitro group is reflected by a