134308-13-7 Usage
Description
Tolcapone, also known as Tasmar, is a yellow, odorless, nonhygroscopic, crystalline compound with the chemical formula 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (pKa=4.78). It is an orally active inhibitor of central and peripheral catechol-O-methyltransferase (COMT) and is used as an adjunct to levodopa/carbidopa for the management of signs and symptoms of Parkinson's disease (PD). Tolcapone is rapidly absorbed after oral administration, highly bound to plasma albumin (>98%), and has low first-pass metabolism. It is almost completely metabolized in the liver before excretion, with 60% being excreted by the kidney. The major metabolite of tolcapone is an inactive glucuronide conjugate. COMT inhibitors, like tolcapone, increase the chronotropic and arrhythmogenic effects of epinephrine.
Uses
1. Used in Antiparkinsonian Applications:
Tolcapone is used as an adjunct to levodopa/carbidopa for the management of signs and symptoms of Parkinson's disease (PD). It acts as an inhibitor of both brain and peripheral catechol O-methyltransferase (COMT) enzymes, enhancing the effectiveness of levodopa therapy and reducing the occurrence of motor fluctuations in PD patients.
2. Used in COMT-Mediated Cell Signaling Studies:
Tolcapone is used as a potent inhibitor of alpha-synuclein and beta-amyloid oligomerization and fibrillogenesis, protecting against extracellular toxicity. It has been utilized in methyltransferase assays in human embryonic kidney 293 cells for studying COMT-mediated cell signaling pathways.
3. Used in Drug Delivery Systems:
Tolcapone is used as a high-affinity binder to transthyretin (TTR), inhibiting TTR aggregation in human plasma and preventing TTR-induced cytotoxicity in vitro. It also stabilizes TTR in mice and humans in vivo. This application is particularly relevant in the development of novel drug delivery systems to enhance the therapeutic outcomes of tolcapone.
4. Used in Inhibition of O-Methylation of Exogenous Polyphenols:
Tolcapone is used as an inhibitor of O-methylation of exogenous polyphenols such as EGCG (epigallocatechin gallate), which is an important aspect in the study of the bioavailability and biological effects of these compounds.
5. Used in Pharmaceutical Industry:
Tolcapone is used as a cell-permeable, orally bioavailable compound in the pharmaceutical industry for the development of drugs targeting COMT inhibition and related pathways, as well as for the treatment of Parkinson's disease and other neurodegenerative disorders.
Originator
Tasmar,Roche
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
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
Check Digit Verification of cas no
The CAS Registry Mumber 134308-13-7 includes 9 digits separated into 3 groups by hyphens. The first part of the number,starting from the left, has 6 digits, 1,3,4,3,0 and 8 respectively; the second part has 2 digits, 1 and 3 respectively.
Calculate Digit Verification of CAS Registry Number 134308-13:
(8*1)+(7*3)+(6*4)+(5*3)+(4*0)+(3*8)+(2*1)+(1*3)=97
97 % 10 = 7
So 134308-13-7 is a valid CAS Registry Number.
InChI:InChI=1/C14H11NO5/c1-8-2-4-9(5-3-8)13(17)10-6-11(15(19)20)14(18)12(16)7-10/h2-7,16,18H,1H3
134308-13-7Relevant articles and documents
Convenient synthesis of tolcapone, a selective catechol-O-methyltransferase inhibitor
Manikumar, Govindarajan,Jin, Chunyang,Rehder, Kenneth S.
, p. 810 - 815 (2008)
A convenient and efficient synthesis of tolcapone from commercial 4-benzyloxy-3-methoxybenzaldehyde is presented. Grignard reaction of 4-benzyloxy-3-methoxybenzaldehyde (1) with p-tolylmagnesium bromide followed by Oppenauer oxidation of the hydroxyl func
Catechol derivatives
-
, (2008/06/13)
Catechol derivatives of the formula STR1 wherein Ra, Rb and Rc have the significance given herein, the ester and ether derivatives thereof which are hydrolyzable under physiological conditions and the pharmaceutically acceptable salts thereof are described and possess valuable pharmacological properties. In particular, they inhibit the enzyme catechol-O-methyltransferase (COMT), a soluble, magnesium-dependent enzyme which catalyses the transference of the methyl group of S-adensoylmethionine to a catechol substrate, whereby the corresponding methyl ethers are formed. Suitable substrates which can be O-methylated by COMT and which can thus be deactivated are, for example, extraneuornal catecholamines and exogeneously-administered therapeutically active substances having a catechol structure. Formula Ia above embraces not only compounds which form part of the invention, but also known compounds; the compounds which form part of the invention can be prepared according to known methods.