Selective inhibitors of monoamine oxidase (MAO‐A and MAO‐B) as probes of its catalytic site and mechanism

Kalgutkar, Amit S.; Castagnoli, Neal; Testa, Bernard

doi:10.1002/med.2610150406

Cited by 90 publications

(85 citation statements)

References 189 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…[2][3][4] MAO-A inhibitors are useful in the therapy of mental disorders, mainly as antidepressants, whereas MAO-B inhibitors are expected to be useful in the therapy of Parkinson's and Alzheimer's disease. 1,5) To date, a number of MAO inhibitors such as coumarins, xanthones, and isoquinoline alkaloids have been isolated from natural products or synthesized.…”

Section: 2)mentioning

confidence: 99%

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

Lee

Hong

Han

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

157

View full text Add to dashboard Cite

Monoamine oxidase (MAO) catalyzes the oxidative deamination of monoamine neurotransmitters such as serotonin, dopamine, and norepinephrine, and appears to play important roles in several psychiatric and neurological disorders. 1,2) MAO has been divided into two subtypes, MAO-A and MAO-B, on the basis of their amino acid sequence, substrate and inhibitor selectivity, and tissue distribution.2-4) MAO-A inhibitors are useful in the therapy of mental disorders, mainly as antidepressants, whereas MAO-B inhibitors are expected to be useful in the therapy of Parkinson's and Alzheimer's disease. 1,5) To date, a number of MAO inhibitors such as coumarins, xanthones, and isoquinoline alkaloids have been isolated from natural products or synthesized. 6-9)Piper longum L. (Piperaceae), a slender aromatic climber, is a native of the Indo-Malayan region and grows wild in the tropical rain forests of India. The extract of the crude drug "Piperis Longi Fructus," the fruits of P. longum, is frequently used in folk medicine to treat bronchial trouble and is used as a carminative and analgesic. 10,11) Piperine was the first amide isolated from Piper species and was reported to display central nervous system depression, antipyretic, and anti-inflammatory activity. 12,13) Moreover, previous studies have demonstrated that piperine and its derivatives present sedative-hypnotic, tranquilizing, and muscle-relaxing actions and can intensify the depressive action of other depressants.14) Based on the aforementioned evidence, it might be suggested that piperine could be useful for the control of CNS-related conditions, including mood disorders and moderate or mild depression states.In the present work, we have investigated the activityguided isolation and inhibitory effect of piperine on MAO activity in mouse brain. We also investigate the antidepressant-like activity of piperine in the in vivo tail suspension test. Results and DiscussionIn our ongoing search for naturally occurring MAO inhibitors, an ethanol extract of the fruits of P. longum exhibited strong inhibitory activity on mouse brain MAO. A bioassay-guided isolation of the extract yielded a known piperidine alkaloid, piperine, as an active component. The structure was identified by physicochemical and spectroscopic methods (mp, UV, IR, MS, 1 H-and 13 C-NMR) and by comparing the data obtained with those of published values (Fig. 1). 15,16) Piperine exhibited 38.0% inhibition of MAO activity at 8 mM, with an IC 50 value of 11.1 mM, which is comparable to iproniazid as a positive control (Table 1). According to the kinetic properties of MAO from the mouse brain, the values of K m and V max by using kynuramine were 72.2Ϯ5.60 mM and 3.97Ϯ0.18 nmol/min/mg protein, respectively (nϭ3) (data not shown).In order to verify the selectivity of the MAO activity, l-deprenyl-pretreated MAO preparation was used for the measurement of MAO-A activity, whereas a clorgyline-pretreated preparation was used for MAO-B. This result indicated that

show abstract

Section: 2)mentioning

confidence: 99%

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

Lee

Hong

Han

et al. 2005

CHEMICAL & PHARMACEUTICAL BULLETIN

157

View full text Add to dashboard Cite

show abstract

“…1 There are two isoforms are found namely MAO-A and MAO-B. 2 MAO plays an essential role in the regulation of significant role in central nervous system activity and contributes to the pathogenesis of human neurodegenerative and depressive disorders. 3 MAO-A is primary type found in fibroblasts, and metabolise the neurotransmitter like Dopamine, Serotonin, epinephrine and norepinephrine.…”

Section: Introductionmentioning

confidence: 99%

QSAR Studies of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors

Singh¹,

Patel²,

Jain³

et al. 2018

Curr. Res. Pharm. Sci.

View full text Add to dashboard Cite

The primary objective of this investigation was to develop a QSAR model for novel series of phenoxy acetamide derivatives as Monoamine Oxidase Inhibitors. The data series were taken from the reported work of Wei Shen et al., 2014. The selected series consists of total 20 compounds, divided into two sets training set having 18 compounds and test set with 2 compounds. All the structures of phenoxy acetamide derivatives were sketched using Chem Office 2001. QSAR models were obtained by using VALSTAT software. The best-developed model showed a good correlative and predictive ability having regression coefficient (r2) of 0.9033 and q2 is 0.8376. For MAO B inhibitor activity, MW has positively correlated. The positive correlation of MW indicates that bulky group or higher molecular weight compounds are important for better MAO enzymes inhibition activity. The negative correlation of HOMO indicated that electrophilic group may increase the activity. The BetaPol also negatively correlated indicated less polar group give more activity. Based on the developed QSAR model, it may be concluded that highest occupied molecular orbital (HOMO) energy, molecular weight and Beta Polarizability are to be considered while designing newer compounds, for their potential MAO inhibitory activity.

show abstract

“…Selective MAO-A inhibitors are used as anti-depressant and anti-anxiety drugs whereas selective MAO-B inhibitors are used to treat Parkinson's disease. [3][4][5] Recently, several research groups have reported chromone derivatives substituted at different positions of the chromone ring and their inhibitory effects towards MAO-A and MAO-B.2,6-12) These reports suggested that structural changes induced by the substitutions on the chromone ring can increase the biological activity of the compound.Azoles such as pyrrole , 13) pyrazole , 14) indole 15) and benzazole 16) containing compounds have also been reported as potent MAO inhibitors. We therefore proposed that chromones bearing an azole moiety should display interesting monoamine oxidase inhibitory activities.…”

mentioning

confidence: 99%

2-Azolylchromone Derivatives as Potent and Selective Inhibitors of Monoamine Oxidases A and B

Takao

Saito

Chikuda

et al. 2016

CHEMICAL & PHARMACEUTICAL BULLETIN

View full text Add to dashboard Cite

A series of 2-azolylchromone derivatives were synthesized and their monoamine oxidase (MAO) A and B inhibitory activities were evaluated. Of the synthesized compounds, compounds 1b, 2b, 4a-c, 5b and 7b showed potent inhibitory activities against MAO-A (IC 50 values, 1b: 0.32 µM; 2b: 0.14 µM; 4a: 0.11 µM; 4b: 0.023 µM; 4c: 0.15 µM; 5b: 0.59 µM; 7b: 0.19 µM) and 4a, c, 5a, c, 6c and 8c for MAO-B (IC 50 values, 4a: 0.028 µM; 4c: 0.019 µM; 5a: 0.73 µM; 5c: 0.28 µM; 6c: 0.28 µM; 8c: 0.27 µM). These data suggest that 6-methoxy substitution favors MAO-A inhibition and 7-methoxy substitution favors MAO-B inhibition. In addition, compound 4b was the most potent inhibitor for MAO-A, and compound 4c for MAO-B. This is the first report identifying 2-azolylchromone derivatives as potent monoamine oxidase inhibitors. These results suggest that the 2-triazolylchromone structure may be a useful scaffold for the design and development of novel monoamine oxidase inhibitors, as evidenced by the activities of 4a-c and 5a-c.Key words 2-azolylchromone; monoamine oxidase A; monoamine oxidase B; inhibitor; structure-activity relationship; 2-triazolylchromone 4H-1-Benzopyran-4-ones (chromones) are an important class of oxygenated heterocyclic compounds that have attracted the attention of organic chemists and biochemists due to their biological activities. The chromone core structure is found in flavones and isoflavones, which are secondary metabolites that are ubiquitous in nature and especially in the plant kingdom, and are present in notable amounts in several species of plants. The chromone scaffold is the pharmacophore of a large number of bioactive molecules of either natural or synthetic origin. The biological effects of these bioactive molecules include anti-inflammatory, anti-tumor and anti-microbial activities, and inhibitory activities towards cyclooxygenases, kinases, phosphatases, aromatases, acetylcholinesterases, and monoamine oxidases. 1,2)The monoamine oxidases A and B (EC 1.4.3.4; MAO-A and MAO-B) are flavoenzymes that play an important role in the oxidative degradation of neurotransmitters such as dopamine, serotonin, and epinephrine. MAOs are found in the outer mitochondrial membrane of various mammalian cell types. MAO-A and MAO-B share approximately 70% sequence identity at the amino acid level and were identified based on their substrate selectivities and inhibitor sensitivities. MAO-A preferentially deaminates serotonin, norepinephrine, and epinephrine and is irreversibly inhibited by clorgyline, whereas MAO-B preferentially deaminates dopamine, β-phenetylamine, and benzylamine and is irreversibly inhibited by R-(−)-deprenyl. MAO inhibitors are important in the treatment of several neurodegenerative diseases. Selective MAO-A inhibitors are used as anti-depressant and anti-anxiety drugs whereas selective MAO-B inhibitors are used to treat Parkinson's disease. [3][4][5] Recently, several research groups have reported chromone derivatives substituted at different positions of the chromone ring and their inhibitory e...

show abstract

Selective inhibitors of monoamine oxidase (MAO‐A and MAO‐B) as probes of its catalytic site and mechanism

Cited by 90 publications

References 189 publications

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

Piperine from the Fruits of Piper longum with Inhibitory Effect on Monoamine Oxidase and Antidepressant-Like Activity

QSAR Studies of 2-Phenoxyacetamide Analogues, a Novel Class of Potent and Selective Monoamine Oxidase Inhibitors

2-Azolylchromone Derivatives as Potent and Selective Inhibitors of Monoamine Oxidases A and B

Contact Info

Product

Resources

About