Description
Tolcapone (134308-13-7) is a catechol O-methyltransferase inhibitor (COMT), inhibiting both brain and peripheral enzymes.1?Potent inhibitor of alpha-synuclein and beta-amyloid oligomerization and fibrillogenesis protecting against extracellular toxicity.2?Binds to transthyretin (TTR) with high affinity (21 to 58 nM) and inhibits TTR aggregation in human plasma and prevents TTR-induced cytotoxicity?in vitro. Stabilizes TTR in mice and humans?in vivo.3?Inhibits O-methylation of exogenous polyphenols such as EGCG.4?Cell permeable. Orally bioavailable.
Chemical Properties
Yellow Solid
Uses
Orally active inhibitor of central and peripheral catechol-O-methyltransferase (COMT). Antiparkinsonian
Definition
ChEBI: Tolcapone is benzophenone substituted on one of the phenyl rings at C-3 and C-4 by hydroxy groups and at C-5 by a nitro group, and on the other phenyl ring by a methyl group at C-4. It is an inhibitor of catechol O-methyltransferase. It has a role as an EC 2.1.1.6 (catechol O-methyltransferase) inhibitor and an antiparkinson drug. It is a member of benzophenones, a member of 2-nitrophenols and a member of catechols.
Preparation
preparation by demethylation of 4-hydroxy-3-methoxy-4′-methyl-5-nitrobenzophenone with hydrobromic acid in refluxing aque-ous acetic acid.
Manufacturing Process
Condensation of 4-benzyloxy-3-methoxybenzaldehyde with 4-lithium-toluene
(prepared from 4-bromotoluene and butyl lithium) leads to the corresponding
benzhydrole. Oxidation of the new formed hydroxyl in benzhydrole gives the
4-benzyloxy-3-methoxyphenyl)-p-tolylmethanone. Treatment of this
compound with hydrogen bromide selectively removes the benzyl ether that is
additionally activated by the transannular carbonyl group. The intermediate is
then nitrated under standart conditions to give the (4-hydroxy-3-methoxy-5-
nitrophenyl)-p-tolylmethanone. A second treatment of the last compound with
hydrogen bromide cleaves the ether group, which is now activated by the
adjacent nitro group. This last step affords the (3,4-dihydroxy-5-nitrophenyl)(4-methylphenyl)methanone.
Therapeutic Function
Antiparkinsonian
General Description
Tolcapone, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Tasmar), is a yellow, odorless, nonhygroscopic,crystalline compound (pKa＝4.78). Tolcapone israpidly absorbed after oral administration. Tolcapone ishighly bound to plasma albumin (＞98%), and its distributionis therefore restricted. Tolcapone has low first-pass metabolism.It is almost completely metabolized in the liver before excretion, and 60% is excreted by the kidney. The majormetabolite of tolcapone is an inactive glucuronide conjugate.COMT inhibitors increase chronotropic and arrhythmogeniceffects of epinephrine.Tolcapone is indicated as an adjunctto levodopa/carbidopa for the management of signs andsymptoms of PD.
Biochem/physiol Actions
Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor. It inhibits both central and peripheral COMT. Tolcapone crosses the blood-brain barrier, and has been used for L-DOPA adjunct therapy in the treatment of Parkinson′s Disease.
Clinical Use
Catechol-o-methyltransferase inhibitor:
Treatment of Parkinson’s disease
Drug interactions
Potentially hazardous interactions with other drugs
Antidepressants: avoid with MAOIs.
Metabolism
Extensively metabolised, mainly by conjugation to
the inactive glucuronide, but methylation by catecholO-methyltransferase to 3-O-methyltolcapone and
metabolism by cytochrome P450 isoenzymes CYP3A4
and CYP2A6 also occurs.
Approximately 60
% of a dose is excreted in the urine with
the remainder appearing in the faeces.
References
1) Manisto?et al.?(1992),?Different in vivo properties of three new inhibitors of catechol O-methyltransferase in the rat; Br, J. Pharmacol.,?105?569
2) Giovanni?et al.?(2010),?Entacapone and tolcapone, two catechol O-methyltransferase inhibitors, block fibril formation of alpha-synuclein and beta-amyloid and protect against amyloid-induced toxicity;?J. Biol. Chem.,?285?14941
3) Sant’Anna?et al.?(2016),?Repositioning tolcapone as a potent inhibitor of transthyretin amyloidogenesis and associated cellular toxicity; Nat. Commun.,?7?10787
4) Forester and Lambert (2015),?The catechol-O-methyltransferase inhibitor, tolcapone, increases the bioavailability of unmethylated (-)-epigallocatechin-3-gallate in mice; Funct. Foods,?17?183
