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

  • G. Zürcher
  • A. Colzi
  • M. Da Prada
Conference paper
Part of the Journal of Neural Transmission book series (NEURAL SUPPL, volume 32)

Summary

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 (15mg/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.

Keywords

COMT Inhibition COMT Activity Peripheral Decarboxylase Inhibitor Intact Amino Acid High COMT Activity 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

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Copyright information

© Springer-Verlag 1990

Authors and Affiliations

  • G. Zürcher
    • 1
  • A. Colzi
    • 1
  • M. Da Prada
    • 1
  1. 1.Pharmaceutical Research DepartmentF. Hoffmann-La Roche LtdBaselSwitzerland

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