134 research outputs found
Caffeine as a lead compound for the design of therapeutic agents for the treatment of Parkinson’s disease
No full textThe current pharmacological therapies for the treatment of Parkinson’s disease are mostly inadequate and recent, improved therapeutic agents are required. Two important molecular targets for the design of anti-parkinsonian therapeutic compounds are the adenosine A2A receptor and the enzyme, monoamine oxidase (MAO) B. Adenosine A2A receptor antagonists are a relatively new class of anti-parkinsonian agents, which act by potentiating dopamine-mediated neurotransmission via dopamine D2 receptors. MAO-B inhibitors are established therapy of Parkinson’s disease and inhibit the MAO-B-catalysed metabolism of dopamine in the brain. This conserves reduced dopamine stores and extends the action of dopamine. A2A antagonism and MAO-B inhibition have also been associated with neuroprotective effects, further establishing roles for these classes of compounds in Parkinson’s disease. Interestingly, caffeine, a known adenosine receptor antagonist, has been recently considered as a lead compound for the design and discovery of A2A antagonists and MAO-B inhibitors. This review summarizes the recent efforts to discover caffeinederived MAO-B inhibitors. The design of caffeine-derived A2A antagonists has been extensively reviewed previously. The prospect of discovering dual-target-directed compounds that act at both targets is also evaluated. Compounds that block the activation and function of both A2A receptors and MAO-B may have a synergistic effect in the treatment of patients with Parkinson’s diseas
Leflunomide, a reversible monoamine oxidase inhibitor
No full textA screening study aimed at identifying inhibitors of the enzyme, monoamine oxidase (MAO), among clinically used drugs have indicated that the antirheumatic drug, leflunomide, is an inhibitor of both MAO isoforms. Leflunomide inhibits human MAO-A and MAO-B and exhibits IC50 values of 19.1 μM and 13.7 μM, respectively. The corresponding Ki values are 17.7 μM (MAO-A) and 10.1 μM (MAO-B). Dialyses of mixtures of the MAO enzymes and leflunomide show that inhibition of the MAOs by leflunomide is reversible. The principal metabolite of leflunomide, teriflunomide (A77 1726), in contrast is not an MAO inhibitor. This study concludes that, although leflunomide is only moderately potent as an MAO inhibitor, isoxazole derivatives may represent a general class of MAO inhibitors and this heterocycle may find application in MAO inhibitor design. In this respect, MAO inhibitors are used in the clinic for the treatment of depressive illness and Parkinson’s disease, and are under investigation as therapy for certain types of cancer, Alzheimer’s disease and age-related impairment of cardiac functio
Novel monoamine oxidase inhibitors: a patent review (2012-2014)
No full textIntroduction: Monoamine oxidase (MAO) inhibitors, despite the initial pharmacological interest, are used in clinic for their antidepressant effect and in the management of Parkinson symptoms, due to the established neuroprotective action. Efficacy and tolerability emerged from large-scale and randomized clinical trials.
Areas covered: Thirty-six patents range from April 2012 to September 2014. The number of chemotypes with inhibitory effects on MAO is truly high (40 synthetic compounds, 22 natural products and 6 plant extracts reported and licensed), and the present review is comprehensive of all compounds, which have been patented for their relevance to clinical medicine in this period range (27 patents). Moreover, some of the collected patents deal with new formulations of compounds endowed with MAO inhibitory properties (two patents) and new therapeutic options/drug associations for already known MAO inhibitors (seven patents).
Expert opinion: The patents reported in this review showed that the interest in this field is constant and mainly devoted to the study of selective MAO-B inhibitors, used as drugs for the treatment of neurological disorders. The development of novel human MAO inhibitors took advantage of the discovery of new therapeutic targets (cancer, hair loss, muscle dystrophies, cocaine addiction and inflammation), the recognized role of MAOs as molecular biomarkers and their activity in other tissue
The synthesis and evaluation of sesamol and benzodioxane derivatives as inhibitors of monoamine oxidase
No full textIn the present study, series of eight sesamol (1,3-benzodioxol-5-ol) and eight benzodioxane (2,3-dihydro-1,4-benzodioxine) derivatives were synthesised and evaluated as inhibitors of recombinant human monoamine oxidase (MAO) A and B. The sesamol and benzodioxane derivatives are structurally related to series of phthalide derivatives, which have previously been found to act as potent reversible MAO inhibitors. The results document that the benzodioxane derivatives, in particular, are potent MAO-B inhibitors with IC50 values ranging from 0.045 to 0.947 μM. IC50 values for the inhibition of MAO-B by the homologous series of sesamol derivatives ranged from 0.164 to 7.29 μM. All compounds evaluated are selective for the MAO-B isoform, with IC50 values for the inhibition of MAO-A ranging from 13.2 to >100 μM. It is further shown that for the most potent MAO-B inhibitor, 6-[(3-bromophenyl)methoxy]-2,3-dihydro-1,4-benzodioxine, inhibition is almost completely reversed by dialysis of enzyme-inhibitor mixtures. It may be concluded that benzodioxane derivatives are promising leads for the design of selective MAO-B inhibitors for the treatment of Parkinson’s diseaseMedical Research Council and National Research Foundation of South Africa (Grant specific unique reference numbers (UID) 85642 and 80647
The interactions of caffeine with monoamine oxidase
No full textAims: Caffeine has been used as a scaffold for the design of inhibitors of monoamine oxidase (MAO) A and B.
Substitution at the C8 position with a variety of moieties yields structures with high MAO inhibition potencies.
Although theMAO inhibitory properties of numerous caffeine derivatives have been characterized, the possibility
that caffeine inhibits the MAOs has not been investigated in detail. Based on the therapeutic applications and
potential adverse effects of MAO inhibition, this study examines the interactions of caffeine with the MAOs.
Main methods: Employing the recombinant human enzymes, the potencies by which caffeine inhibits the in vitro
catalytic activities of theMAOs were recorded and expressed as the IC50 and Ki values. The reversibility of inhibition
was determined by measuring the recovery of enzyme activity after dialysis of enzyme–caffeine mixtures.
Key findings: Caffeine acts as a MAO inhibitor with Ki values of 0.70 mMand 3.83 mMfor the inhibition of MAO-A
andMAO-B, respectively. The results showthat caffeine binds reversibly and competitively to bothMAO enzymes.
Significance: Although structural modifications of caffeine lead to highly potent MAO inhibitors, caffeine is a weak
inhibitor of MAO-A and MAO-B. At plasma concentrations (approximately 1–10 μM) achieved by normal human
consumption, theMAO inhibitory potencies of caffeine are unlikely to be of pharmacological relevance in humans.
The MAO inhibitory effects of caffeine should however be taken into consideration when using this drug in vitro
and in tissue culture experiments where higher doses and concentrations of caffeine are often used
Nitrocatechol derivatives of chalcone as inhibitors of monoamine oxidase and Catechol-O-Methyltransferase
No full textIntroduction: The efficacy of L-dopa in the treatment of Parkinson’s disease depends on its metabolic conversion to dopamine in the brain, however extensive peripheral metabolism of L-dopa diminishes its availability for uptake into the brain. L-Dopa is extensively decarboxylated in the gastrointestinal tract and peripheral tissues by Aromatic L-Amino Acid Decarboxylase (AADC), and AADC inhibitors are thus frequently combined with L-dopa therapy. When AADC is inhibited, 3-Omethylation Catalysed by Catechol-O-Methyltransferase (COMT) becomes a dominant metabolic pathway for L-dopa, and COMT inhibitors may thus also be used as adjuncts to L-dopa in Parkinson’s disease. Monoamine Oxidase (MAO), in turn, metabolises dopamine in the brain, and MAO-B inhibitors may exert a dopamine sparing effect in the brain.
Materials & Methods: Based on the roles of COMT and MAO in the metabolism of L-dopa and dopamine, the present study attempts to discover novel dual inhibitors of these enzymes. For this purpose, nitrocatechol derivatives of chalcone were synthesised and evaluated as inhibitors of COMT and MAO. The chalcone class of compounds is well known to potently inhibit MAO-B, while nitrocatechol derivatives (e.g. tolcapone and entacapone) are clinically used COMT inhibitors.
Results: The results document that all of the derivatives are high potency in vitro inhibitors of rat liver COMT with IC50 values ranging from 0.07 to 0.29 μM. Under these experimental conditions, tolcapone and entacapone display IC50 values of 0.26 µM and 0.25 µM, respectively. The chalcones are less potent as inhibitors of MAO with the most potent inhibitor possessing a Ki of 4.6 µM for the in vitro inhibition of human MAO-B.
Conclusion: This study shows that nitrocatechol derivatives of chalcone may act as COMT and MAO-B inhibitors, and proposes a general strategy for further enhancing MAO-B inhibition while retaining the potent COMT inhibition activity of this clas
Inhibition of monoamine oxidase by selected phenylalkylcaffeine analogues
No full textObjectives Caffeine represents a useful scaffold for the design of monoamine
oxidase (MAO) type B inhibitors. Specifically, substitution on the C8 position
yields structures which are high-potency MAO-B inhibitors. To explore the
structure–activity relationships of MAO-B inhibition by caffeine-derived compounds,
this study examines the MAO inhibitory properties of a series of
phenylalkylcaffeine analogues.
Methods Employing the recombinant human enzymes, the potencies (IC50
values) by which the caffeine analogues inhibit MAO-A and MAO-B were measured.
The reversibility of inhibition of a selected inhibitor was determined by
measuring the recovery of enzyme activity after dilution and dialysis of enzymeinhibitor
mixtures.
Key findings The results document that the phenylalkylcaffeine analogues are
reversible and selective MAO-B inhibitors with a competitive mode of inhibition.
The most potent analogue, 8-(7-phenylheptyl)caffeine, exhibits IC50 values for
the inhibition of MAO-A and MAO-B of 3.01 μm and 0.086 μm, respectively.
Increasing the length of the alkyl side chain leads to enhanced MAO-A and
MAO-B inhibitory potency while introduction of a carbonyl group reduces
MAO-B inhibitory potency.
Conclusions Phenylalkylcaffeines represent a new class of high-potency MAO-B
inhibitors with the longer alkyl side chains yielding enhanced inhibitory activity.
Such compounds may represent useful leads for the development of antiparkinsonian
therapiesSupported in part by the
Medical Research Council and National Research Foundation
(NRF) of South Africa (Grant specific unique reference
numbers (UID) 85642 and 80647
A Review of the Pharmacological Properties of 3,4-dihydro-2(1H)- quinolinones
No full textThe 3,4-dihydro-2(1H)-quinolinone moiety is present in a number of pharmacologically active compounds. These include FDA approved drugs such as cilostazol, carteolol and aripiprazole as well as numerous experimental compounds. Compounds containing the 3,4-dihydro-2(1H)-quinolinone moiety also exhibit a variety of activities in both the peripheral and central tissues, which includes phosphodiesterase inhibition, blocking of β-adrenergic receptors, antagonism of vasopressin receptors and interaction with serotonin and dopamine receptors. Based on its versatility in drug design and action, this paper reviews the pharmacological actions of compounds containing the 3,4-dihydro-2(1H)- quinolinone scaffold with emphasis being placed on the most important and significant members of each activity clas
Evaluation of natural and synthetic 1,4-naphthoquinones as inhibitors of monoamine oxidase
No full textPrevious reports have documented that 1,4-naphtho-
quinones act as inhibitors of the monoamine oxidase
(MAO) enzymes. In particular, fractionation of the
extracts of cured tobacco leafs has led to the charac-
terization of 2,3,6-trimethyl-1,4-naphthoquinone, a non-
selective MAO inhibitor. To derive structure–activity
relationships for MAO inhibition by the 1,4-naphthoqui-
none class of compounds, this study investigates the
human MAO inhibitory activities of fourteen structurally
diverse 1,4-naphthoquinones of natural and synthetic
origin. Of these, 5,8-dihydroxy-1,4-naphthoquinone
was found to be the most potent inhibitor with an IC
50
value of 0.860 l M for the inhibition of MAO-B. A related
compound, shikonin, inhibits both the MAO-A and
MAO-B isoforms with IC
50
values of 1.50 and 1.01 lM,
respectively. It is further shown that MAO-A and MAO-
B inhibition by these compounds is reversible by dialy-
sis. In this respect, kinetic analysis suggests that the
modes of MAO inhibition are competitive. This study
contributes to the discovery of novel MAO inhibitors,
which may be useful in the treatment for disorders
such as Parkinson’s disease, depressive illness, con-
gestive heart failure and cance
The evaluation of 1,4-benzoquinones as inhibitors of human monoamine oxidase
No full textThe monoamine oxidase (MAO) enzymes are of considerable pharmacological interest and inhibitors are used in the clinic for the treatment of major depressive disorder and Parkinson's disease. A limited number of studies have shown that the quinone class of compounds possesses MAO inhibition properties. Most notable among these is a report that 2,3,6-trimethyl-1,4-naphthoquinone (TMN), present in extracts of cured tobacco leafs, is a non-selective inhibitor of both MAO isoforms. An older study reports that 1,4-benzoquinone inhibits MAO-A and MAO-B from human synaptosomes. Both 1,4-naphthoquinones and 1,4-benzoquinone are reported to inhibit the MAOs with a reversible mode of action. Since the MAO inhibition properties of additional members of the 1,4-benzoquinone class of compounds have not yet been explored, the present study investigates a small series of four 1,4-benzoquinones which incorporate phenyl, benzyl, benzyloxy and cyclopentyl monosubstitution on C2. The 1,4-benzoquinones were found to be moderately potent MAO inhibitors with IC50 values of 5.03–13.2 μM (MAO-A) and 3.69–23.2 μM (MAO-B). These values are comparable to those recorded for 1,4-benzoquinone of 4.82 μM (MAO-A) and 10.2 μM (MAO-B). Of interest however, is the finding that the 1,4-benzoquinones are irreversible inhibitors of MAO-A since prolonged incubation results in near complete inhibition, and enzyme activity is not recovered by dialysis. MAO-B is much less sensitive to inactivation by the 1,4-benzoquinones. These findings are discussed with reference to a possible mechanism by which irreversible inhibition occurs. It may be concluded that irreversible 1,4-benzoquinone-derived inhibitors may act as probes for investigating quinone reactive sites in the MAO
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