Favorable effect of catechol-O-methyltransferase inhibition by OR-462 in experimental models of Parkinson's disease.
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.
Lindén
I B
IB
Orion Pharmaceutica, Research Center, Espoo, Finland.
Nissinen
E
E
Etemadzadeh
E
E
Kaakkola
S
S
Männistö
P
P
Pohto
P
P
D000818:Animals; D002230:Carbidopa / Q000008:administration & dosage; D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols / Q000494:pharmacology*; D003342:Corpus Striatum / Q000032:analysis; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007659:Ketones / Q000494:pharmacology*; D007980:Levodopa / Q000008:administration & dosage / Q000378:metabolism; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy*; D010422:Pentanones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D012399:Rotation
D065098:Catechol O-Methyltransferase Inhibitors; D002396:Catechols; D007659:Ketones; D010422:Pentanones; D007980:Levodopa; C057364:nitecapone; D002230:Carbidopa