Inhibition of monoamine oxidase B by selected benzimidazole and caffeine analogues

Berg, Deidré van den; Zoellner, Kevin Robert; Ogunrombi, Modupe; Malan, Sarel F.; Terre’Blanche, Gisella; Castagnoli, Neal; Bergh, Jacobus J.; Petzer, Jacobus P.

doi:10.1016/j.bmc.2007.03.046

Cited by 65 publications

(15 citation statements)

References 26 publications

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“…To determine the structural requirements necessary for methylxanthines to act as MAO-B inhibitors, various substituted methylxanthines were evaluated as MAO-B inhibitors. 27,28,108,109 Analogous to what has been observed with A 2A antagonists, substitution of the caffeine ring at C-8 with a variety of groups yielded compounds endowed with more potent MAO-B inhibition activities than caffeine. Also, analogous to A 2A antagonists, the styryl side chain was found to be especially efficient in enhancing the MAO-B inhibition potency of caffeine-derived inhibitors.…”

Section: Methylxanthines As Dual-target-directed Drugsmentioning

confidence: 83%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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Summary:Inadequacies of the current pharmacotherapies to treat Parkinson's disease (PD) have prompted efforts to identify novel drug targets. The adenosine A 2A receptor is one such target. Antagonists of this receptor (A 2A antagonists) are considered promising agents for the symptomatic treatment of PD. Evidence suggests that A 2A antagonists may also have neuroprotective properties that may prevent the development of the dyskinesia that often complicates levodopa treatment. Because the therapeutic benefits of A 2A antagonists are additive to that of dopamine replacement therapy, it may be possible to reduce the dose of the dopaminergic drugs and therefore the occurrence of side effects. Inhibitors of monoamine oxidase (MAO)-B also are considered useful tools for the treatment of PD. When used in combination with levodopa, inhibitors of MAO-B may enhance the elevation of dopamine levels after levodopa treatment, particularly when used in early stages of the disease when dopamine production may not be so severely compromised. Furthermore, MAO-B inhibitors may also possess neuroprotective properties in part by reducing the damaging effect of dopamine turnover in the brain. These effects of MAO-B inhibitors are especially relevant when considering that the brain shows an age-related increase in MAO-B activity. Based on these observations, dual-target-directed drugs, compounds that inhibit MAO-B and antagonize A 2A receptors, may have value in the management of PD. This review summarizes recent efforts to develop such dual-acting drugs using caffeine as the lead compound.

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Section: Methylxanthines As Dual-target-directed Drugsmentioning

confidence: 83%

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

et al. 2009

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“…The improved inhibition potency and selectivity of CSC compared to caffeine has been explained by the possibility that ( E )-styrylcaffeines span both the substrate and entrance cavities of MAO-B. This would allow for more productive van der Waals contacts with active site residues in both cavities that would lead to more potent inhibition 11,13. In contrast, caffeine is expected to bind to either the substrate or entrance cavity, leaving the other cavity unoccupied.…”

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confidence: 99%

Inhibition of monoamine oxidase by (E)-styrylisatin analogues

Walt

Milczek

Malan

et al. 2009

Bioorganic & Medicinal Chemistry Letters

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Previous studies have shown that (E)-8-(3-chlorostyryl)caffeine (CSC) is a specific reversible inhibitor of human monoamine oxidase B (MAO-B) and does not bind to human MAO-A. Since the small molecule isatin is a natural reversible inhibitor of both MAO-B and MAO-A, (E)-5-styrylisatin and (E)-6-styrylisatin analogues were synthesized in an attempt to identify inhibitors with enhanced potencies and specificities for MAO-B. The (E)-styrylisatin analogues were found to exhibit higher binding affinities than isatin with the MAO preparations tested. The (E)-5-styrylisatin analogues bound more tightly than the (E)-6 analogue although the latter exhibits the highest MAO-B selectivity. Molecular docking studies with MAO-B indicate that the increased binding affinity exhibited by the (E)-styrylisatin analogues, in comparison to isatin, is best explained by the ability of the styrylisatins to bridge both the entrance cavity and the substrate cavity of the enzyme. Experimental support for this model is shown by the weaker binding of the analogues to the Ile199Ala mutant of human MAO-B. The lower selectivity of the (E)-styrylisatin analogues between MAO-A and MAO-B, in contrast to CSC, is best explained by the differing relative geometries of the aromatic rings for these two classes of inhibitors. KeywordsMonoamine oxidase A; Monoamine oxidase B; Reversible inhibitor; Isatin; (E)-5-Styrylisatin; (E)-6-StyrylisatinThe oxidative deamination reaction catalyzed by monoamine oxidase B (MAO-B) is one of the major catabolic pathway of dopamine in the brain. Inhibitors of this enzyme lead to enhanced dopaminergic neurotransmission and are currently used in the symptomatic treatment of Parkinson's disease (PD). 1-4 Furthermore, MAO-B inhibitors also may exert a neuroprotective effect by reducing the concentrations of potentially hazardous by-products produced by MAO-B-catalyzed dopamine oxidation. 5 Considering that the human brain exhibits an age-related increase in MAO-B activity, inhibition of this enzyme is especially relevant in the treatment of PD. 6-8 The endogenous small molecule isatin (1) (Fig. 1) has been reported to be a moderately potent inhibitor of human MAO-B with an enzyme-inhibitor *Corresponding author. Tel.: +27 18 2992206; fax: +27 18 2994243. E-mail adress: E-mail: jacques.petzer@nwu.ac.za (J.P. Petzer). Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. Another small molecule, caffeine (2), is a weak inhibitor of MAO-B with a K i value of 3.6 mM. The inhibition potency of caffeine is substantially increased by substitution at C-8 of the caffeinyl ring with a styryl...

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“…After the completion of the dropping, a white precipitate was formed and stirred for 2 h, collected by filtration, and crystallized from acetate to obtain white crystal substituted styrol-formamidobenzoic acid (8a-g). 1,[17][18][19] To a solution of 1,3-dimethyl-5,6-diaminouracil 4 (3.50 mmol) and EDAC (5.11 mmol) in dioxane-H 2 O (1 : 1, 40 mL), the appropriate substituted styrol-formamidobenzoic acid 8a-g (3.81 mmol) was added. The pH of the suspension was adjusted to 5 with 2 M aqueous hydrochloric acid and stirring was continued for an additional 8 h. The reaction mixture was neutralized with 1 M aqueous sodium hydroxide, cooled to 0°C, and the resulting precipitate was collected by filtration.…”

Section: Methodsmentioning

confidence: 99%

“…N-(4-(1,3-Dimethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)phenyl)-3-(4-fluorophenyl)acrylamide (9f): Yield 43.7%, mp >300°C. [17][18][19] Iodomethane (0.40 mmol) was added to a stirred suspension of (0.20 mmol) 1,3-dimethyl-(E)-8-substituted styrolformamido-7H-xanthinyl analogues 9a-g and potassium carbonate (0.50 mmol) in N,N-dimethylformamide (10 mL). Stirring was continued at 60°C for 1 h, and the insoluble materials were removed by filtration, and sufficient water was added to the filtrate to precipitate the product collected by filtration.…”

Section: General Procedures Of 13-dimethyl-(e)-8-substituted Styrol-fmentioning

confidence: 99%

Design, Synthesis and Inhibitory Activities of 8-(Substituted styrol-formamido)phenyl-xanthine Derivatives on Monoamine Oxidase B

Nian

Qin

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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The design and synthesis of two series of 8-(substituted styrol-formamido)phenyl-xanthine derivatives are described. Their in vitro monoamine oxidase B (MAO-B) inhibition were tested and the effect of substituents on the N-7, phenyl and the substituted positions are discussed. It was observed that compound 9b displayed significant MAO-B inhibition activity and selectivity, fluorine substitution plays a key role in the selectivity of MAO-B inhibition, and the styrol-formamido group at position-3′ may enhance the activity and selectivity of 8-phenyl-xanthine analogues. These results suggest that such compounds may be utilized for the development of new candidate MAO-B inhibitors for treatment of Parkinson's disease.Key words xanthine derivative; monoamine oxidase B inhibition activity; substituent effect Parkinson's disease (PD) is a neurodegenerative disorder characterized pathologically by a marked loss of dopaminergic nigrostriatal neurons and clinically by disabling movement disorders.1) Currently, the therapy of PD is largely focused on dopamine replacement strategies with the dopamine precursor levodopa and dopamine agonist drugs. Although these strategies are highly effective in controlling the disease at the early stages, drug-related complications are associated with long-term treatment. The inadequacies of dopamine replacement therapy have prompted the research of alternative drug targets. 2-5)Monoamine oxidase (MAO) is an integral protein of the outer mitochondrial membrane, and exist in two forms, namely, monoamine oxidase A (MAO-A) and MAO-B. MAO-A preferentially deaminates aromatic monoamines such as the neurotransmitters serotonin (5-HT), noradrenaline (NA), andadrenaline (A); MAO-B is one of the most important key enzymes in metabolic pathways in vivo and plays mainly three roles: firstly, MAO-B decomposes dopamine into 3,4-dihydroxyphenyl acetic acid and homovanillic acid, meanwhile producing the neurotoxic H 2 O 2 . Secondly, MAO-B inactivates p-phenylethylamine which has the ability to stimulate secrection and reuptake function of dopamine. Thirdly, in the precence of MAO-B, catalyzed oxidation of 1-methyl-4-phenyl-1,2,3,6-terahydropyridine (MPTP) to intermediate 1-methyl-4-phenyl-2,3-dihydropyridin-1-ium (MPDP + ) and then to 1-methyl-4-phenylpyridin-1-ium (MPP + )with neurotoxicity occurs. Together these suggest that inhibiting the action of MAO-B can not only reduce the degradation of dopamine and reuptake, improving the concentration of dopamine in the brain, but also lower levels of H 2 O 2 , and MPP + to enhance neuroprotective properties. [6][7][8][9][10][11][12] Recently, xanthine and its derivatives were reported to produce little or no inhibition of MAO-B. In the last decade, when introducing phenyl at position-8, 8-phenyl xanthine exhibited MAO-B inhibition activity in vitro with a inhibition constant (K i ) value of 86.2 μM.2) Petzer et al. found a series of 8-styryl xanthine analogues exhibiting more powerful inhibition of MAO-B than 8-phenyl xanthine analogues (CSC K i =100 nM; KW6...

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Inhibition of monoamine oxidase B by selected benzimidazole and caffeine analogues

Cited by 65 publications

References 26 publications

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Dual-Target–Directed Drugs that Block Monoamine Oxidase B and Adenosine A Receptors for Parkinson's Disease

Inhibition of monoamine oxidase by (E)-styrylisatin analogues

Design, Synthesis and Inhibitory Activities of 8-(Substituted styrol-formamido)phenyl-xanthine Derivatives on Monoamine Oxidase B

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