A novel hypothesis-generating computational workflow utilizing reverse pharmacophore mapping-A drug repurposing perspective of istradefylline towards major depressive disorder.

Background And Purpose: Drug repurposing (DR) offers a compelling alternative to traditional drug discovery's lengthy, resource-intensive process. DR is the process of identifying alternative clinical applications for pre-approved drugs as a low-risk and low-cost strategy. Computational approaches are crucial during the early hypothesis-generating stage of DR.

On the basis of sex: male vs. female rat adenosine A/A receptor affinity.

Objective: To ensure reproducibility in biomedical research, the biological variable sex must be reported; yet a reason for using male (instead of female) rodents is seldom given. In our search for novel adenosine receptor ligands, our research group routinely determines a test compound's binding affinities at male Sprague-Dawley rat (r) adenosine A and A receptors via in vitro radioligand binding studies. This pilot study compared the binding affinities of four adenosine receptor ligands (frequently used as reference standards) at male and female adenosine rA and rA receptors.

Untargeted Metabolomics Reveals the Potential Antidepressant Activity of a Novel Adenosine Receptor Antagonist.

Depression is the most common mental illness, affecting approximately 4.4% of the global population. Despite many available treatments, some patients exhibit treatment-resistant depression.

Drug Discovery Strategies Identified ADMET Properties of Decoquinate RMB041 and Its Potential Drug Targets against Mycobacterium tuberculosis.

The highly adaptive cellular response of Mycobacterium tuberculosis to various antibiotics and the high costs for clinical trials, hampers the development of novel antimicrobial agents with improved efficacy and safety. Subsequently, drug screening methods are more commonly being used for the discovery and development of drugs, and have been proven useful for predicting the pharmacokinetics, toxicities, and targets, of prospective new antimicrobial agents. In this investigation we used a reversed target fishing approach to determine potential hit targets and their possible interactions between M.

C2-substituted quinazolinone derivatives exhibit A and/or A adenosine receptor affinities in the low micromolar range.

Antagonists of the adenosine receptors (A and A subtypes) are widely researched as potential drug candidates for their role in Parkinson's disease-related cognitive deficits (A subtype), motor dysfunction (A subtype) and to exhibit neuroprotective properties (A subtype). Previously the benzo-α-pyrone based derivative, 3-phenyl-1H-2-benzopyran-1-one, was found to display both A and A adenosine receptor affinity in the low micromolar range. Prompted by this, the α-pyrone core was structurally modified to explore related benzoxazinone and quinazolinone homologues previously unknown as adenosine receptor antagonists.

Methoxy substituted 2-benzylidene-1-indanone derivatives as A and/or A AR antagonists for the potential treatment of neurological conditions.

A prior study reported on hydroxy substituted 2-benzylidene-1-indanone derivatives as A and/or A antagonists for the potential treatment of neurological conditions. A lead compound () was identified with both A and A affinity in the micromolar range. The current study explored the structurally related methoxy substituted 2-benzylidene-1-indanone derivatives with various substitutions on ring A and B of the benzylidene indanone scaffold in order to enhance A and A affinity.

2-Benzylidene-1-Indanone Analogues as Dual Adenosine A1/A2a Receptor Antagonists for the Potential Treatment of Neurological Conditions.

Previous studies explored 2-benzylidine-1-tetralone derivatives as innovative adenosine A and A receptor antagonists for alternative non-dopaminergic treatment of Parkinson's disease. This study's aim is to investigate structurally related 2-benzylidene-1-indanones with substitutions on ring A and B as novel, potent and selective adenosine A and A receptor blockers. 2-Benzylidene-1-indanone derivatives were synthesised via acid catalysed aldol condensation reactions and evaluated via radioligand binding assays to ascertain structure activity relationships to govern A and A AR affinity.

8-(3-phenylpropyl)-1,3,7-triethylxanthine is a synthetic caffeine substitute with stronger metabolic modulator activity.

Caffeine is one of the most worldwide consumed methylxanthines. It is well-known for its thermogenic and cell metabolism modulating effects. Based on methylxanthines' chemical structure, 8-(3-phenylpropyl)-1,3,7-triethylxanthine (PTX) is a novel adenosine antagonist with higher receptor affinity than caffeine.

Benzopyrone represents a privilege scaffold to identify novel adenosine A/A receptor antagonists.

Adenosine receptor antagonists are under investigation as potential drug candidates for the treatment of certain cancers, neurological disorders, depression and potentially improve tumour immunotherapy. The benzo-γ-pyrone scaffold is well-known in medicinal chemistry with diverse pharmacological activities attributed to them, however, their therapeutic potential as adenosine receptor antagonists have not been investigated in detail. To expand on the structure-activity relationships, the present study explored the adenosine A and A receptor binding affinities of a selected series of benzo-γ-pyrone analogues.

Imidazo[1,2-α]pyridines possess adenosine A receptor affinity for the potential treatment of cognition in neurological disorders.

Previous research has shown that bicyclic 6:5-fused heteroaromatic compounds with two N-atoms have variable degrees of adenosine A receptor antagonistic activity. Prompted by this imidazo[1,2-α]pyridine analogues were synthesized and evaluated for their adenosine A and A receptor affinity via radioligand binding studies and subjected to a GTP shift assay to determine its adenosine A receptor agonistic or antagonistic functionality. Imidazo[1,2-α]pyridine, the parent scaffold, was found devoid of affinity for the adenosine A and A receptors.

Evaluation of 2-benzylidene-1-tetralone derivatives as antagonists of A and A adenosine receptors.

Antagonists of the adenosine receptors (A and A ) are thought to be beneficial in neurological disorders, such as Alzheimer's and Parkinson's disease. The aim of this study was to explore 2-benzylidene-1-tetralone derivatives as antagonists of A and/or A adenosine receptors. In general, the test compounds were found to be selective for the A adenosine receptor, with only three test compounds possessing affinity for both the A and A adenosine receptor.

Benzyloxynitrostyrene analogues - A novel class of selective and highly potent inhibitors of monoamine oxidase B.

This study examines a series of novel 3-benzyloxy-β-nitrostyrene analogues as a novel class of inhibitors of the monoamine oxidase (MAO) enzymes. MAO inhibitors are considered useful for the treatment of depression and Parkinson's disease, and have recently attracted attention as potential therapeutic agents for a range of disorders including Alzheimer's disease, prostate cancer and certain cardiomyopathies. This study shows that the 3-benzyloxy-β-nitrostyrene analogues are potent inhibitors of the MAO-B isoform with IC values in the nanomolar range (39-565 nM).

Discovery of 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine derivatives as novel adenosine A and A receptor antagonists.

Based on a previous report that a series of 8-(phenoxymethyl)-xanthines may be promising leads for the design of A adenosine receptor antagonists, selected novel and known 1,3-diethyl-7-methyl-8-(phenoxymethyl)-xanthine and 1,3,7-trimethyl-8-(phenoxymethyl)-xanthine analogs were synthesized and evaluated for their A and A adenosine receptor affinity. Generally, the study compounds exhibited affinity for both the A and A adenosine receptors. Replacement of the 1,3-dimethyl-substition with a 1,3-diethyl-substition pattern increased A and A binding affinity.

2-Aminopyrimidines as dual adenosine A1/A2A antagonists.

In this study thirteen 2-aminopyrimidine derivatives were synthesised and screened as potential antagonists of adenosine A1 and A2A receptors in order to further investigate the structure activity relationships of this class of compounds. 4-(5-Methylfuran-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (8m) was identified as a compound with high affinities for both receptors, with an A2AKi value of 6.34 nM and an A1Ki value of 9.

1,3,7-Triethyl-substituted xanthines--possess nanomolar affinity for the adenosine A1 receptor.

Adenosine A1 receptors are attracting great interest as drug targets for their role in cognitive deficits. Antagonism of the adenosine A1 receptor may offer therapeutic benefits in complex neurological diseases, such as Alzheimer's and Parkinson's disease. The aim of this study was to discover potential selective adenosine A1 receptor antagonists.

The adenosine receptor affinities and monoamine oxidase B inhibitory properties of sulfanylphthalimide analogues.

Based on a report that sulfanylphthalimides are highly potent monoamine oxidase (MAO) B selective inhibitors, the present study examines the adenosine receptor affinities and MAO-B inhibitory properties of a series of 4- and 5-sulfanylphthalimide analogues. Since adenosine antagonists (A1 and A2A subtypes) and MAO-B inhibitors are considered agents for the therapy of neurodegenerative disorders such as Parkinson's disease and Alzheimer's disease, dual-target-directed drugs that antagonize adenosine receptors and inhibit MAO-B may have enhanced therapeutic value. The results document that the sulfanylphthalimide analogues are selective for the adenosine A1 receptor over the A2A receptor subtype, with a number of compounds also possessing MAO-B inhibitory properties.

The adenosine A(2A) antagonistic properties of selected C8-substituted xanthines.

The adenosine A2A receptor is considered to be an important target for the development of new therapies for Parkinson's disease. Several antagonists of the A2A receptor have entered clinical trials for this purpose and many research groups have initiated programs to develop A2A receptor antagonists. Most A2A receptor antagonists belong to two different chemical classes, the xanthine derivatives and the amino-substituted heterocyclic compounds.

Sulfanylphthalonitrile analogues as selective and potent inhibitors of monoamine oxidase B.

It has recently been reported that nitrile containing compounds frequently act as potent monoamine oxidase B (MAO-B) inhibitors. Modelling studies suggest that this high potency inhibition may rely, at least in part, on polar interactions between nitrile functional groups and polar moieties within the MAO-B substrate cavity. In an attempt to identify potent and selective inhibitors of MAO-B and to contribute to the known structure-activity relationships of MAO inhibition by nitrile containing compounds, the present study examined the MAO inhibitory properties of series of novel sulfanylphthalonitriles and sulfanylbenzonitriles.

Novel sulfanylphthalimide analogues as highly potent inhibitors of monoamine oxidase B.

Monoamine oxidase (MAO) plays an essential role in the catabolism of neurotransmitter amines. The two isoforms of this enzyme, MAO-A and -B, are considered to be drug targets for the therapy of depression and neurodegenerative diseases, respectively. Based on a recent report that the phthalimide moiety may be a useful scaffold for the design of potent MAO-B inhibitors, the present study examines a series of 5-sulfanylphthalimide analogues as potential inhibitors of both human MAO isoforms.

Treatment of an adrenomyeloneuropathy patient with Lorenzo's oil and supplementation with docosahexaenoic acid--a case report.

This is a case report of adrenomyeloneuropathy (AMN), the adult variant of adrenoleukodystryphy (ALD). The diagnoses in the patient, aged 34, was confirmed via increased serum very long chain fatty acid concentration (VLCFA). Treatment started with the cholesterol lowering drug, atorvastatin, followed by add-on therapy with Lorenzo's oil (LO) and finally supplementation with docosahexaenoic acid (DHA).