Favorable effect of catechol-O-methyltransferase inhibition by OR-462 in experimental models of Parkinson's disease.

Abstract

A selective catechol-O-methyltransferase inhibitor, OR-462, was studied for its ability to affect pharmacokinetic properties of L-dopa after the p.o. administration of the inhibitor to rats and mice. When OR-462 was given to rats at the dose range of 0.3 to 30 mg/kg in conjunction with L-dopa and carbidopa, a dose-related and long-lasting (greater than 5 hr) increase in striatal L-dopa and dopamine levels as well as a reduction in 3-O-methyldopa levels were shown. For a 50% reduction of the 3-O-methyldopa levels a dose of 6 mg/kg of OR-462 was needed. The increase in striatal homovanillic acid, an O-methylated metabolite of dopamine which poorly penetrates the blood brain barrier, indicates that O-methylation was not inhibited in the brain. In order to get the same dopamine levels in striatum the L-dopa dose could be lowered to one-fourth when OR-462 was added. The L-dopa-sparing effect of OR-462 given p.o. was also demonstrated in two behavioral parkinsonian models. OR-462 given at doses of 3 to 30 mg/kg in conjunction with L-dopa and carbidopa, dose-dependently potentiated the L-dopa-induced reversal of hypoactivity in reserpinized mice. Likewise, the same doses of OR-462 caused a marked potentiation of L-dopa-induced contralateral turning behavior in rats with unilateral nigrostriatal lesions produced by 6-hydroxydopamine. The data suggest a possible beneficial effect of OR-462 in the therapy of Parkinson's disease.

• Authors: I B Lindén, E Nissinen, E Etemadzadeh, S Kaakkola, P Männistö, P Pohto
• Journal: The Journal of pharmacology and experimental therapeutics (J Pharmacol Exp Ther) Vol. 247 Issue 1 Pg. 289-93 (Oct 1988) ISSN: 0022-3565 [Print] United States
• PMID: 3171977 (Publication Type: Journal Article)

Chemical References

• Catechol O-Methyltransferase Inhibitors
• Catechols
• Ketones
• Pentanones
• Levodopa
• nitecapone
• Carbidopa

Topics

• Animals
• Carbidopa (administration & dosage)
• Catechol O-Methyltransferase Inhibitors
• Catechols (pharmacology)
• Corpus Striatum (analysis)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Ketones (pharmacology)
• Levodopa (administration & dosage, metabolism)
• Male
• Mice
• Motor Activity (drug effects)
• Parkinson Disease (drug therapy)
• Pentanones (pharmacology)
• Rats
• Rats, Inbred Strains
• Rotation