Skip to main content
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1992 Mar;105(3):569–574. doi: 10.1111/j.1476-5381.1992.tb09020.x

Different in vivo properties of three new inhibitors of catechol O-methyltransferase in the rat.

P T Männistö 1, P Tuomainen 1, R K Tuominen 1
PMCID: PMC1908463  PMID: 1628144

Abstract

1. We compared three new catechol O-methyltransferase (COMT) inhibitors (OR-611, Ro 40-7592 and CGP 28014; 10 and 30 mg kg-1, i.p.) in male rats given levodopa (L-DOPA, 50 mg kg-1, i.p.) and carbidopa ((-)-L-alpha-methyl dopa, 50 mg kg-1, i.p.). In some studies pretreatment with pargyline (80 mg kg-1, i.p.) was used to block the function of monoamine oxidase (MAO). 2. Decreases of hypothalamic and striatal 3-O-methyl-dopa (3-OMD) levels were used as measures of the inhibition of peripheral COMT. The inhibition of brain COMT activity was estimated by decreases of hypothalamic and striatal homovanillic acid (HVA) and 3-methoxytyramine (3-MT; after pargyline) levels. 3. The three COMT inhibitors studied had different individual characteristics. OR-611 was primarily a peripherally acting COMT inhibitor, decreasing 3-OMD levels in the striatum (to 31-52%) and in the hypothalamus (to 16-27%) both in the control and pargyline-treated animals at 1 and 3 h. It did not have any effect on brain HVA and 3-MT. 3. Ro 40-7592 was a broad spectrum COMT inhibitor decreasing striatal and hypothalamic 3-OMD (always to less than 30%), HVA (to less than 50%) and 3-MT levels (to less than 23%) significantly both at 1 and 3 h. It was more potent than OR-611. 4. CGP 28014 functioned as a weak COMT inhibitor in the periphery inhibiting 3-OMD formation only at 3 h. In contrast, it was fairly potent in decreasing the brain HVA and 3-MT levels at 1 h (to 37-22% and 42-35% in the striatum, and to 57-33% and 64-35% in the hypothalamus, respectively) but not at 3 h. Since CGP 28014, unlike OR-611 and Ro 40-7592, did not generally increase the brain DOPA, dopamine or DOPAC levels, it was not a typical COMT inhibitor.

Full text

PDF
569

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Baldessarini R. J. Inhibition of catechol-O-methyl transferase by L-dopa and decarboxylase inhibitors. J Pharm Pharmacol. 1972 Jan;24(1):78–80. doi: 10.1111/j.2042-7158.1972.tb08873.x. [DOI] [PubMed] [Google Scholar]
  2. Cedarbaum J. M. Clinical pharmacokinetics of anti-parkinsonian drugs. Clin Pharmacokinet. 1987 Sep;13(3):141–178. doi: 10.2165/00003088-198713030-00002. [DOI] [PubMed] [Google Scholar]
  3. Etemadzadeh E., Koskinen L., Kaakkola S. Computerized rotometer apparatus for recording circling behavior. Methods Find Exp Clin Pharmacol. 1989 Jun;11(6):399–407. [PubMed] [Google Scholar]
  4. Glowinski J., Iversen L. L. Regional studies of catecholamines in the rat brain. I. The disposition of [3H]norepinephrine, [3H]dopamine and [3H]dopa in various regions of the brain. J Neurochem. 1966 Aug;13(8):655–669. doi: 10.1111/j.1471-4159.1966.tb09873.x. [DOI] [PubMed] [Google Scholar]
  5. Kato T., Dong B., Ishii K., Kinemuchi H. Brain dialysis: in vivo metabolism of dopamine and serotonin by monoamine oxidase A but not B in the striatum of unrestrained rats. J Neurochem. 1986 Apr;46(4):1277–1282. doi: 10.1111/j.1471-4159.1986.tb00650.x. [DOI] [PubMed] [Google Scholar]
  6. Kopin I. J. Catecholamine metabolism: basic aspects and clinical significance. Pharmacol Rev. 1985 Dec;37(4):333–364. [PubMed] [Google Scholar]
  7. Männistö P. T., Kaakkola S. New selective COMT inhibitors: useful adjuncts for Parkinson's disease? Trends Pharmacol Sci. 1989 Feb;10(2):54–56. doi: 10.1016/0165-6147(89)90075-8. [DOI] [PubMed] [Google Scholar]
  8. Männistö P. T., Kaakkola S., Nissinen E., Linden I. B., Pohto P. Properties of novel effective and highly selective inhibitors of catechol-O-methyltransferase. Life Sci. 1988;43(18):1465–1471. doi: 10.1016/0024-3205(88)90258-5. [DOI] [PubMed] [Google Scholar]
  9. Männistö P. T., Kaakkola S. Rationale for selective COMT inhibitors as adjuncts in the drug treatment of Parkinson's disease. Pharmacol Toxicol. 1990 May;66(5):317–323. doi: 10.1111/j.1600-0773.1990.tb00756.x. [DOI] [PubMed] [Google Scholar]
  10. Männistö P. T., Tuomainen P. Effect of high single doses of levodopa and carbidopa on brain dopamine and its metabolites: modulation by selective inhibitors of monoamine oxidase and/or catechol-O-methyltransferase in the male rat. Naunyn Schmiedebergs Arch Pharmacol. 1991 Oct;344(4):412–418. doi: 10.1007/BF00172580. [DOI] [PubMed] [Google Scholar]
  11. Männistö P. T., Tuomainen P., Toivonen M., Törnwall M., Kaakkola S. Effect of acute levodopa on brain catecholamines after selective MAO and COMT inhibition in male rats. J Neural Transm Park Dis Dement Sect. 1990;2(1):31–43. doi: 10.1007/BF02251244. [DOI] [PubMed] [Google Scholar]
  12. Nissinen E., Lindén I. B., Schultz E., Kaakkola S., Männistö P. T., Pohto P. Inhibition of catechol-O-methyltransferase activity by two novel disubstituted catechols in the rat. Eur J Pharmacol. 1988 Aug 24;153(2-3):263–269. doi: 10.1016/0014-2999(88)90614-0. [DOI] [PubMed] [Google Scholar]
  13. Oreland L., Arai Y., Stenström A. The effect of deprenyl (selegiline) on intra- and extraneuronal dopamine oxidation. Acta Neurol Scand Suppl. 1983;95:81–85. doi: 10.1111/j.1600-0404.1983.tb01518.x. [DOI] [PubMed] [Google Scholar]
  14. Trendelenburg U. The uptake and metabolism of 3H-catecholamines in rat cerebral cortex slices. Naunyn Schmiedebergs Arch Pharmacol. 1989 Mar;339(3):293–297. doi: 10.1007/BF00173580. [DOI] [PubMed] [Google Scholar]
  15. Wagner J., Vitali P., Palfreyman M. G., Zraika M., Huot S. Simultaneous determination of 3,4-dihydroxyphenylalanine, 5-hydroxytryptophan, dopamine, 4-hydroxy-3-methoxyphenylalanine, norepinephrine, 3,4-dihydroxyphenylacetic acid, homovanillic acid, serotonin, and 5-hydroxyindoleacetic acid in rat cerebrospinal fluid and brain by high-performance liquid chromatography with electrochemical detection. J Neurochem. 1982 May;38(5):1241–1254. doi: 10.1111/j.1471-4159.1982.tb07897.x. [DOI] [PubMed] [Google Scholar]
  16. Waldmeier P. C., Baumann P. A., Feldtrauer J. J., Hauser K., Bittiger H., Bischoff S., von Sprecher G. CGP 28014, a new inhibitor of cerebral catechol-O-methylation with a non-catechol structure. Naunyn Schmiedebergs Arch Pharmacol. 1990 Sep;342(3):305–311. doi: 10.1007/BF00169442. [DOI] [PubMed] [Google Scholar]
  17. Waldmeier P. C., De Herdt P., Maitre L. Effects of the COMT inhibitor, CGP 28014, on plasma homovanillic acid and O-methylation of exogenous L-dopa in the rat. J Neural Transm Suppl. 1990;32:381–386. doi: 10.1007/978-3-7091-9113-2_52. [DOI] [PubMed] [Google Scholar]
  18. Zürcher G., Colzi A., Da Prada M. Ro 40-7592: inhibition of COMT in rat brain and extracerebral tissues. J Neural Transm Suppl. 1990;32:375–380. doi: 10.1007/978-3-7091-9113-2_51. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES