Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The structure of catechol O-methyltransferase (COMT) has been recently characterized and a series of new and selective COMT inhibitors developed. 2. Entacapone, nitecapone and tolcapone are nitrocatechol-type potent COMT inhibitors in vitro (Ki in nanomolar range). They are also very selective for COMT and active in vivo even after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo. 3. In animal studies, these compounds inhibit effectively the O-methylation of L-dopa, thus improving its bioavailability and brain penetration and potentiating its behavioural effects. 4. Entacapone and nitecapone have mainly a peripheral effect whereas tolcapone and CGP 28014 also inhibit O-methylation in the brain. 5. In man, entacapone, nitecapone and tolcapone all inhibit dose dependently the COMT activity in erythrocytes. These COMT inhibitors also decrease the amount of COMT dependent metabolites of adrenaline and noradrenaline in plasma. 6. In human volunteers, entacapone, tolcapone and CGP 28014 improve the bioavailability of L-dopa and inhibit the formation of 3-O-methyldopa. 7. In the first clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiate and prolong the therapeutic effect of L-dopa.
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PMID:General properties and clinical possibilities of new selective inhibitors of catechol O-methyltransferase. 783 24

The effects of three new, selective inhibitors of catechol O-methylation were compared regarding their potentiation of L-3,4-dihydroxyphenylalanine (L-dopa)/carbidopa-induced contralateral circling behaviour in male rats. Some studies were also done with amphetamine, which causes ipsilateral turning. A peripherally acting compound, entacapone, a peripherally and centrally acting compound, tolcapone, and an atypical compound, CGP 28014 (3, 10 or 30 mg/kg) increased the effect of L-dopa/carbidopa (2/30 or 5/30 mg/kg) on contralateral circling by 2.0-6.1-fold. Addition of clorgyline (3 mg/kg) did not increase, but rather decreased, the entacapone (3 mg/kg) and L-dopa/carbidopa (2/30 or 5/30 mg/kg)-induced peak circling. Amphetamine (2.5 mg/kg)-induced ipsilateral circling behaviour was not affected by tolcapone (30 mg/kg). We conclude that L-dopa-induced circling behaviour is enhanced and prolonged by all types of catechol O-methyltransferase inhibitors regardless of their brain penetration. The results suggest that catechol O-methylation inhibitors may be beneficial as L-dopa adjuncts in the treatment of patients with Parkinson's disease.
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PMID:Effects of three types of catechol O-methylation inhibitors on L-3,4-dihydroxyphenylalanine-induced circling behaviour in rats. 811 26

A series of new and selective catechol-O-methyltransferase (COMT) inhibitors have been developed. Entacapone, nitecapone and to1capone are nitrocatechol- type agents that are potent COMT inhibitors in vitro and are active in vivo after oral administration. CGP 28014 is a pyridine derivative that is active only in vivo.In animal studies, these compounds inhibit effectively the O-methylation of levodopa, thus improving its bioavailability and brain penetration, and potentiating its behavioural effects. Entacapone and nitecapone have mainly peripheral effects, whereas to1capone and CGP 280 14 inhibit O-methylation also in the brain. In human volunteers, entacapone, nitecapone and tolcapone inhibit dose-dependently COMT activity of erythrocytes. COMT inhibitors also decrease the levels of COMT-dependent metabolites of adrenaline (epinephrine) and noradrenaline (norepinephrine) in plasma.Entacapone, to1capone and CGP 28014 improve the bioavailability of levodopa and inhibit the formation of 3-0-methyldopa in human volunteers. In initial clinical studies in patients with Parkinson's disease, both entacapone and tolcapone potentiated and prolonged the therapeutic effects of levodopa.
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PMID:Clinical Potential of Catechol-OMethyltransferase (COMT) Inhibitors as Adjuvants in Parkinson's Disease. 2752 May 16