Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues

J Neural Transm Suppl. 1990;32:375-80. doi: 10.1007/978-3-7091-9113-2_51.

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.

MeSH terms

  • Animals
  • Benserazide / pharmacology
  • Benzophenones / pharmacology*
  • Biological Availability
  • Brain / drug effects
  • Brain / enzymology*
  • Catechol O-Methyltransferase / blood
  • Catechol O-Methyltransferase Inhibitors*
  • Chromatography, High Pressure Liquid
  • Electrochemistry
  • Erythrocytes / drug effects
  • Erythrocytes / enzymology
  • Half-Life
  • In Vitro Techniques
  • Levodopa / metabolism
  • Male
  • Nitrophenols
  • Norepinephrine / metabolism
  • Rats
  • Rats, Inbred Strains
  • Tolcapone
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism

Substances

  • Benzophenones
  • Catechol O-Methyltransferase Inhibitors
  • Nitrophenols
  • Tyrosine
  • Levodopa
  • Benserazide
  • Tolcapone
  • Catechol O-Methyltransferase
  • 3-methoxytyrosine
  • Norepinephrine