1,721,154 research outputs found
Expanding the repertoire of methanocarba nucleosides from purinergic signaling to diverse targets
No full textNucleoside derivatives are well represented as pharmaceuticals due to their druglike physicochemical properties, and some nucleoside drugs are designed to act on receptors. The purinergic signaling pathways for extracellular nucleosides and nucleotides, consisting of adenosine receptors, P2Y/P2X receptors for nucleotides, and enzymes such as adenosine (ribo)kinase, have been extensively studied. A general modification, i.e. a constrained, bicyclic ring system (bicyclo[3.1.0]hexane, also called methanocarba) substituted in place of a furanose ring, can increase nucleoside/nucleotide potency and/or selectivity at purinergic and antiviral targets and in interactions at diverse and unconventional targets. Compared to other common drug discovery scaffolds containing planar rings, methanocarba nucleosides display greater sp3 character (i.e. more favorable as drug-like molecules) and can manifest as sterically-constrained North (N) or South (S) conformations. Initially weak, off-target interactions of (N)-methanocarba adenosine derivatives were detected as leads that were structurally optimized to enhance activity and selectivity toward target proteins that normally do not recognize nucleosides. By this approach, novel modulators for 5HT(2) serotonin and κ-opioid receptors, dopamine (DAT) and ATP-binding cassette (ABC) transporters were found, and previously undetected antiviral activities were revealed. Thus, through methanocarba nucleoside synthesis, structure–activity relationships, and multi-target pharmacology, a robust purinergic receptor scaffold has been repurposed to satisfy the pharmacophoric requirements of various GPCRs, enzymes and transporters
Purinergic Pharmacology
No full textThis eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contac
Purinergic Pharmacology
No full textThis eBook is a collection of articles from a Frontiers Research Topic. Frontiers Research Topics are very popular trademarks of the Frontiers Journals Series: they are collections of at least ten articles, all centered on a particular subject. With their unique mix of varied contributions from Original Research to Review Articles, Frontiers Research Topics unify the most influential researchers, the latest key findings and historical advances in a hot research area! Find out more on how to host your own Frontiers Research Topic or contribute to one as an author by contacting the Frontiers Editorial Office: frontiersin.org/about/contac
Adenosine Receptor Antagonists in Neurodegenerative Diseases
No full textBACKGROUND: Alzheimer’s disease (AD) is the most common form of dementia worldwide, with approximately 6 million cases reported in America in 2020. The clinical signs of AD include cognitive dysfunction, apathy, anxiety and neuropsychiatric signs, and pathogenetic mechanisms that involve amyloid peptide-β extracellular accumulation and tau hyperphosphorylation. Unfortunately, current drugs to treat AD can provide only symptomatic relief but are not disease-modifying molecules able to revert AD progression. The endogenous modulator adenosine, through A(2A) receptor activation, plays a role in synaptic loss and neuroinflammation, which are crucial for cognitive impairment and memory damage. OBJECTIVE: In this review, recent advances covering A(2A) adenosine receptor antagonists will be extensively reviewed, providing a basis for the rational design of future A(2A) inhibitors. METHODS: Herein, the literature on A(2A) adenosine receptors and their role in synaptic plasticity and neuroinflammation, as well as the effects of A(2A) antagonism in animal models of AD and in humans, are reviewed. Furthermore, current chemical and structure-based strategies are presented. RESULTS: Caffeine, the most widely consumed natural product stimulant and an A(2A) antagonist, improves human memory. Similarly, synthetic A(2A) receptor antagonists, as described in this review, may provide a means to fight AD. CONCLUSION: This review highlights the clinical potential of A(2A) adenosine receptor antagonists as a novel approach to treat patients with AD
Novel fluorescent hA3 adenosine receptor antagonists.
No full textActivation of the Gi protein-coupled A3 adenosine receptor (AR) is associated with anticancer, antiischemic and anti-inflammatory effects. hA3 AR antagonists are being examined as promising agents for the treatment of glaucoma.1
Fluorescent probes are useful tools to investigate specific subcellular components in cells, tissues and organisms. In high throughput screening, fluorescent ligands represents a safer, more powerful and more versatile alternative to radioligands.2
We have recently reported a series of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidine (PTP) based fluorophore-conjugated hA3 AR antagonists.3 Unfortunately, none of them reached affinities in the nM range. Here we report a novel series of PTP based fluorophore-conjugated hA3 AR antagonist with an additional pharmacophoric group at the 5-position, in order to obtain more potent hA3 AR antagonists.
References
1. Müller, C.E.; Jacobson, K.A. Recent developments in adenosine receptor ligands and their potential as novel drugs. Biochim. Biophys. Acta 2011, 1808, 1290-1308.
2. Kuder,K.; Kiec-Kononowicz, K. Fluorescent GPCR ligands as new tools in pharmacology. Curr. Med. Chem. 2008, 15, 2132–2143.
3. Kozma, E.; Kumar, T.S.; Federico, S.; Phan, K.; Balasubramanian, R.; Gao, Z.G.; Paoletta, S.; Moro, S.; Spalluto, G.; Jacobson, K.A. Novel fluorescent antagonist as a molecular probe in A3 adenosine receptor binding assays using flow cytometry. Biochem. Pharmacol. 2012, 83, 1552-1561
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Synthesis and Effect of Conformationally Locked Carbocyclic Guanine Nucleotides on Dynamin
Full text linkGuanine nucleotides can flip between a North and South conformation in the ribose moiety. To test the enzymatic activity of GTPases bound to nucleotides in the two conformations, we generated methanocarba guanine nucleotides in the North or South envelope conformations, i.e., (N)-GTP and (S)-GTP, respectively. With dynamin as a model system, we examined the effects of (N)-GTP and (S)-GTP on dynamin-mediated membrane constriction, an activity essential for endocytosis. Dynamin membrane constriction and fission activity are dependent on GTP binding and hydrolysis, but the effect of the conformational state of the GTP nucleotide on dynamin activity is not known. After reconstituting dynamin-mediated lipid tubulation and membrane constriction in vitro, we observed via cryo-electron microscopy (cryo-EM) that (N)-GTP, but not (S)-GTP, enables the constriction of dynamin-decorated lipid tubules. These findings suggest that the activity of dynamin is dependent on the conformational state of the GTP nucleotide. However, a survey of nucleotide ribose conformations associated with dynamin structures in nature shows almost exclusively the (S)-conformation. The explanation for this mismatch of (N) vs. (S) required for GTP analogues in a dynamin-mediated process will be addressed in future studies
Pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines to develop functionalized ligands to target adenosine receptors: fluorescent ligands as an example
No full textA series of adenosine receptor antagonists bearing a reactive linker was developed. Functionalization of these derivatives is useful to easily obtain multi-target ligands, receptor probes, drug delivery systems, and diagnostic or theranostic systems. The pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine scaffold was chosen as a pharmacophore for the adenosine receptors. It was substituted at the 5 position with reactive linkers of different lengths. Then, these compounds were used to synthesise probes for the adenosine receptors by functionalization with a fluorescent moiety. Both series of compounds were evaluated for their binding at the four adenosine receptor subtypes. Different affinity and selectivity profiles were observed towards hA1, hA2A and hA3 adenosine receptors. In particular, fluorescent compounds behave as dual hA2A/hA3 ligands. Computational studies suggested different binding modes for developed compounds at the three receptors. Both molecular docking and supervised molecular dynamics (SuMD) simulations confirmed that the preferred binding mode at the single receptor was driven by the substitution present at the 5 position. Obtained results rationalized the compounds' binding profile at the adenosine receptors and pave the way for the development of more potent conjugable and conjugated ligands targeting these membrane receptors
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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