title: Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues.
abstract: A random biochemical screening followed by lead optimization culminated in the discovery of Ro 40-7592 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone). Ro 40-7592 was found to inhibit COMT in a competitive fashion both in the CNS and in the periphery (Ki for the liver enzyme = 30 nM). Ro 40-7592 (30 mg/kg p.o.) combined with benserazide (15 mg/kg p.o.) and a low dose of L-DOPA (10 mg/kg p.o.) almost completely blocked (for about 6 h) the formation of 3-O-methyldopa (3-OMD) in brain and plasma, producing a long-lasting increase of L-DOPA in plasma and a parallel marked increase of L-DOPA and dopamine in the brain. Ro 40-7592, combined with peripheral decarboxylase inhibitors and L-DOPA (as in Madopar and Sinemet), will offer substantial advantages in the therapy of Parkinson's disease, i.e. enhanced bioavailability and prolonged plasma half-life of L-DOPA, pronounced DOPA sparing effect and blockade of 3-OMD formation.
authors.affiliation: Pharmaceutical Research Department, F. Hoffmann-La Roche Ltd, Basel, Switzerland.
authors.forename: G
authors.initials: G
authors.lastname: Zürcher
authors.forename: A
authors.initials: A
authors.lastname: Colzi
authors.forename: M
authors.initials: M
authors.lastname: Da Prada
mesh_terms: D000818:Animals; D001545:Benserazide / Q000494:pharmacology; D001577:Benzophenones / Q000494:pharmacology*; D001682:Biological Availability; D001921:Brain / Q000187:drug effects / Q000201:enzymology*; D002394:Catechol O-Methyltransferase / Q000097:blood; D065098:Catechol O-Methyltransferase Inhibitors; D002851:Chromatography, High Pressure Liquid; D004563:Electrochemistry; D004912:Erythrocytes / Q000187:drug effects / Q000201:enzymology; D006207:Half-Life; D066298:In Vitro Techniques; D007980:Levodopa / Q000378:metabolism; D008297:Male; D009596:Nitrophenols; D009638:Norepinephrine / Q000378:metabolism; D051381:Rats; D011919:Rats, Inbred Strains; D000077867:Tolcapone; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism
chemical_list: D001577:Benzophenones; D065098:Catechol O-Methyltransferase Inhibitors; D009596:Nitrophenols; D014443:Tyrosine; D007980:Levodopa; D001545:Benserazide; D000077867:Tolcapone; D002394:Catechol O-Methyltransferase; C008404:3-methoxytyrosine; D009638:Norepinephrine