The Lipophilicity Behavior of Three Catechol-O-methyltransferase (COMT) Inhibitors and Simple Analogues

Novaroli, Laura; Doulakas, Géraldine Bouchard; Reist, Marianne; Rolando, Barbara; Fruttero, Roberta; Gasco, Alberto; Carrupt, Pierre‐Alain

doi:10.1002/hlca.200690007

Cited by 16 publications

(13 citation statements)

References 24 publications

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“…However, recent studies demonstrate that tolcapone can be used with benefit when the liver function is actively monitored (79,80). Although these two compounds share the same pharmacophore, their pharmacokinetic profiles are remarkably different (81). Indeed, studies with rats have shown that tolcapone has a longer duration of action than entacapone and is both a central and peripheral COMT inhibitor, whereas entacapone is essentially a peripheral inhibitor (82)(83)(84)(85).…”

Section: Discussionmentioning

confidence: 99%

Entacapone and Tolcapone, Two Catechol O-Methyltransferase Inhibitors, Block Fibril Formation of α-Synuclein and β-Amyloid and Protect against Amyloid-induced Toxicity

Giovanni

Eleuteri

Paleologou

et al. 2010

Journal of Biological Chemistry

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127

108

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Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease (AD). There is considerable consensus that the increased production and/or aggregation of ␣-synuclein (␣-syn) plays a central role in the pathogenesis of PD and related synucleinopathies. Current therapeutic strategies for treating PD offer mainly transient symptomatic relief and aim at the restitution of dopamine levels to counterbalance the loss of dopaminergic neurons. Therefore, the identification and development of drug-like molecules that block ␣-synuclein aggregation and prevent the loss of dopaminergic neurons are desperately needed to treat or slow the progression of PD. Here, we show that entacapone and tolcapone are potent inhibitors of ␣-syn and ␤-amyloid (A␤) oligomerization and fibrillogenesis, and they also protect against extracellular toxicity induced by the aggregation of both proteins. Comparison of the anti-aggregation properties of entacapone and tolcapone with the effect of five other catechol-containing compounds, dopamine, pyrogallol, gallic acid, caffeic acid, and quercetin on the oligomerization and fibrillization of ␣-syn and A␤, demonstrate that the catechol moiety is essential for the antiamyloidogenic activity. Our findings present the first characterization of the anti-amyloidogenic properties of tolcapone and entacapone against both ␣-synuclein and A␤42 and highlight the potential of this class of nitro-catechol compounds as antiamyloidogenic agents. Their inhibitory properties, mode of action, and structural properties suggest that they constitute promising lead compounds for further optimization. Parkinson disease (PD)2 is the second most common neurodegenerative disorder after Alzheimer disease (AD), affecting nearly 1-2% of the population 65 years and older. A characteristic early pathological change associated with PD is the selective loss of dopaminergic neurons of the substantia nigra pars compacta and other areas of the brain resulting in the degeneration of the nigro-striatal tract and loss of dopamine (DA) (1). Current therapeutic strategies for treating PD offer mainly transient symptomatic relief by aiming to restore the loss of dopamine by "dopamine replacement therapy." This is accomplished through the administration of levodopa (L-DOPA), a direct precursor of DA and other drugs that increase the lifetime of DA by slowing its metabolism. Catechol O-methyltransferase inhibitors (ICOMT), monoamine oxidase B inhibitors (IMAO B), and peripheral aromatic L-amino acid decarboxylase inhibitors (IAADC) are used as adjunctive medications to L-DOPA to slow DA degradation and increase the availability of brain DA (Scheme

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Section: Discussionmentioning

confidence: 99%

Entacapone and Tolcapone, Two Catechol O-Methyltransferase Inhibitors, Block Fibril Formation of α-Synuclein and β-Amyloid and Protect against Amyloid-induced Toxicity

Giovanni

Eleuteri

Paleologou

et al. 2010

Journal of Biological Chemistry

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127

108

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“…The partition coefficient (Log P) of the ionized form of 32 has been determined to be -0.4 in a mixture of 1,2-dichloroethane-water. 98 The low lipophilicity 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 24 of 32 at physiological pH can also explain its limited passage across the BBB. In addition to its low aqueous solubility and lipophilicity, the enzymatic stability of 32 is also limited.…”

Section: Tight-binding Inhibitorsmentioning

confidence: 96%

“…98,99 At the higher pH values (pH ≥ 5) found in the small intestine, 32 exists in the ionized form, which limits its passage through the intestinal wall. The partition coefficient (Log P) of the ionized form of 32 has been determined to be -0.4 in a mixture of 1,2-dichloroethane-water.…”

Section: Tight-binding Inhibitorsmentioning

confidence: 99%

Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

2014

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Catechol O-methyltransferase (COMT) is the enzyme responsible for the O-methylation of endogenous neurotransmitters and of xenobiotic substances and hormones incorporating catecholic structures. COMT is a druggable biological target for the treatment of various central and peripheral nervous system disorders, including Parkinson's disease, depression, schizophrenia, and other dopamine deficiency-related diseases. The purpose of this perspective is fourfold: (i) to summarize the physiological role of COMT inhibitors in central and peripheral nervous system disorders; (ii) to provide the history and perspective of the medicinal chemistry behind the discovery and development of COMT inhibitors; (iii) to discuss how the physicochemical properties of recognized COMT inhibitors are understood to exert influence over their pharmacological properties; and (iv) to evaluate the clinical benefits of the most relevant COMT inhibitors.

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“…Enzymatic hydrolysis rates were measured as described above and the protective activity of the test compounds for each concentration was calculated as the percentage of ALP activity obtained in the absence of oxidation (considered to be 100%). The antioxidant capacity of test compounds was expressed as pIC 50 (Àlog IC 50 ) and was calculated by curve fitting according to the classical sigmoidal dose-response equation using Prism V4.0 (GraphPad Software, Inc., San Diego, CA). All pIC 50 values were determined in triplicate from at least ten test compound concentrations.…”

Section: Determination Of Antioxidant Activity Of Compoundsmentioning

confidence: 99%

“…The good antioxidant properties to protect proteins from loss of activity induced by peroxyl radicals of entacapone and tolcapone emerged in this work might thus provide an enhanced symptomatic efficacy in the treatment of PD, these compounds being able to pass the blood brain barrier (BBB). 50 On the other hand, the antioxidant properties of nitecapone are not relevant for central nervous system (CNS) protection against oxidative damage since it does not penetrate in the brain. 30,51 Convenience of the Developed Screening Assay to Assess Functional Damage to Proteins…”

Section: Antioxidant Protection Of Alp By Comt Inhibitors: An Examplementioning

confidence: 99%

Novel screening assay for antioxidant protection against peroxyl radical‐induced loss of protein function

Bertolini

Novaroli

Carrupt

et al. 2007

Journal of Pharmaceutical Sciences

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The Lipophilicity Behavior of Three Catechol-O-methyltransferase (COMT) Inhibitors and Simple Analogues

Cited by 16 publications

References 24 publications

Entacapone and Tolcapone, Two Catechol O-Methyltransferase Inhibitors, Block Fibril Formation of α-Synuclein and β-Amyloid and Protect against Amyloid-induced Toxicity

Entacapone and Tolcapone, Two Catechol O-Methyltransferase Inhibitors, Block Fibril Formation of α-Synuclein and β-Amyloid and Protect against Amyloid-induced Toxicity

Medicinal Chemistry of CatecholO-Methyltransferase (COMT) Inhibitors and Their Therapeutic Utility

Novel screening assay for antioxidant protection against peroxyl radical‐induced loss of protein function

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