Catechol-O-methyltransferase inhibition by U-0521 increases striatal utilization of levodopa

  • Avinoam Reches
  • De-hua Jiang
  • Stanley Fahn


The effects of U-0521, a catechol-O-methyltransferase (COMT) inhibitor, were studied on this enzyme activity and on Dopa metabolism in rat striatum. In vivo maximal inhibition (95%) of COMT activity was obtained at 5 min with enzyme recovery to 64% of basal activity at 120 min. When injected in increasing doses U-0521 (200 mg·kg−1) inhibited, at 10 min, COMT activity by 85% with an IC50=80 mg·kg−1. In rats pretreated with U-0521 and then with DOPA the accumulation of 3-O-methyldopa (OMD) in the plasma was essentially blocked while Dopa, dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) accumulation in the striatum was significantly higher than in DOPA treated controls. U-0521, a potent COMT inhibitor, enhances the availability and utilization of levodopa in the brain and may thus be helpful in future treatment of parkinsonian patients.

Key words

Catechol-O-methyltransferase DOPA Striatum Parkinson's disease 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Bartholini G, Kuruma I, Pletscher A (1971) 3-O-Methyldopa, a new precursor of dopamine. Nature 230:533–534Google Scholar
  2. Bartholini G, Kuruma I, Pletscher A (1972) The metabolic pathways of L-3-O-methyldopa. J Pharmacol Exp Ther 183:65–72Google Scholar
  3. Calne DB, Reid JL, Vakil SD (1972) Parkinsonism treated with 3-O-methyldopa. Clin Pharmacol Ther 14:386–389Google Scholar
  4. Chase TN, Ng LKY (1972) O-Methyldopa in parkinsonism. Neurology 22:417Google Scholar
  5. Davis GC, Kissinger PT, Shoup RE (1981) Strategies for determination of serum or plasma norepinephrine by reverse-phase liquid chromatography. Anal Chem 53:156–159Google Scholar
  6. Ericsson AD (1971) Potentiation of the L-Dopa effect in man by the use of catechol-O-methyltransferase inhibitors. J Neurol Sci 14:193–197Google Scholar
  7. Fahn S (1974) “On-off” phenomenon with levodopa therapy in parkinsonism. Neurology 24:431–441Google Scholar
  8. Fahn S, Comi R, Snider SR, Prasad ALN (1979) Effect of catechol-O-methyl-transferase inhibitor, U-0521, with levodopa administration. Biochem Pharmacol 28:1221–1225Google Scholar
  9. Feuerstein C, Tanche M, Serre F, Gavend M, Pellat J, Perret J (1977) Does O-methyldopa play a role in levodopa-induced dyskinesia? Acta Neurol Scand 56:79–82Google Scholar
  10. Giles RE, Miller JW (1967) A comparison of certain properties of catechol-O-methyltransferase to those of adrenergic beta receptors. J Pharmacol Exp Ther 156:201–206Google Scholar
  11. Guldberg HC, Marsden CA (1975) Catechol-O-methyl transferase: Pharmacological aspects and physiological role. Pharmacol Rev 27:135–206Google Scholar
  12. Hardebo JE, Owman C (1980) Barrier mechanisms for neurotransmitter monoamines and their precursors at the blood brain interface. Ann Neurol 8:1–11Google Scholar
  13. Hefti F (1979) A simple, sensitive method for measuring 3,4-dihydroxyphenylacetic acid and homovanillic acid in rat brain tissue using high performance liquid chromatography with electrochemical detection. Life Sci 25:775–781Google Scholar
  14. Keller R, Oke A, Mefford I, Adams RN (1976) Liquid chromatographic analysis of catecholamines. Routine assay for regional brain mapping. Life Sci 19:995–1004Google Scholar
  15. Muenter MD, Sharpless NS, Tyce GM (1972) Plasma 3-O-methyldopa in l-Dopa therapy of Parkinson's disease. Mayo Clin Proc 47:389–395Google Scholar
  16. Muenter MD, Di Napoli RP, Sharpless NS, Tyce GM (1973) 3-O-Methyldopa, l-Dopa and trihexylphenidyl in the treatment of Patkinson disease. Mayo Clin Proc 48:173–183Google Scholar
  17. Prasad ALN, Fahn S (1974) 3-O-Methyl metabolites of catecholamines: Automated fluorometric assay and their plasma levels in patients receiving levodopa and carbidopa. Biochem Med 9:136–147Google Scholar
  18. Quiram DR, Weinshilboum RM (1976) Catechol-O-methyltransferase in rat erythrocyte and three other tissues: Comparison of biochemical properties after removal of inhibitory calcium. J Neurochem 27:1197–1203Google Scholar
  19. Raymond FA, Weinshilboum RM (1975) Microassay of human erythrocyte catechol-O-methyltransferase: Removal of inhibitory calcium ion with chelating resin. Clin Chim Acta 58:185–194Google Scholar
  20. Reches A, Fahn S (1981a) Inhibition of Dopa uptake and metabolism in rat striatum by O-methyl Dopa. Soc Neurosci Abstr 7:206 1981Google Scholar
  21. Reches A, Fahn S (1981b) O-Methyldopa interferes with striatal utilization of levodopa. Ann Neurol 10:94–95Google Scholar
  22. Reches A, Fahn S (1982a) The inhibitory effect of 3-O-methyldopa on striatal utilization of levodopa in the rat. Ann Neurol (in press)Google Scholar
  23. Reilly DK, Rivera-Calimlin L, Van Dyke D (1980) Catechol-O-methyl transferase activity. A determinant of levodopa response. Clin Pharmacol Ther 28:278–286Google Scholar
  24. Rivera-Calimlim L, Tandon D, Anderson F, Joynt R (1977) The clinical picture and plasma levodopa metabolite profile of parkinsonian nonresponders. Treatment with levodopa and decarboxylase inhibitor. Arch Neurol (Chicago) 34:228–232Google Scholar
  25. Sharpless NS, McCann DS (1971) Dopa and 3-O-methyldopa in cerebrospinal fluid of parkinsonian patients during treatment with oral l-Dopa. Clin Chim Acta 31:155–169Google Scholar
  26. Sharpless N, Muenter MD, Tyce GM, Owen CA (1972) 3-Methoxy-4-hydroxyphenyl alanine (3-O-methyldopa) in plasma during oral l-dopa therapy of patients with Parkinson's disease. Clin Chim Acta 37:359–369Google Scholar
  27. Shoulson I, Glaubiger GA, Chase TN (1975) On-off response. Neurology 25:1144–1148Google Scholar
  28. Sweet RD, McDowell FH, (1974) Plasma DOPA concentrations and the “on-off” effect after chronic treatment of Parkinson's disease. Neurology 24:953–956Google Scholar
  29. Wade LA, Katzman R (1975) 3-O-Methyldopa uptake and inhibition of l-Dopa at the blood brain barrier. Life Sci 17:131–136Google Scholar

Copyright information

© Springer-Verlag 1982

Authors and Affiliations

  • Avinoam Reches
    • 1
  • De-hua Jiang
    • 1
  • Stanley Fahn
    • 1
  1. 1.Department of Neurology, College of Physicians and SurgeonsColumbia UniversityNew YorkUSA

Personalised recommendations