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Diseño in silico y síntesis de análogos de baclofen como posibles agonistas del receptor gabab
No full textRESUMEN.
El ácido γ-aminobutírico 1 (GABA), es el
neurotransmisor inhibitorio más importante en el sistema
nervioso central (SNC) y ejerce su acción fisiológica mediante la
interacción con receptores específicos, denominados GABAA,
GABAB y GABAC.
Baclofeno, análogo de GABA -p-clorofenil sustituido, es
el único ligando agonista de los receptores GABAB aprobado por
la FDA para tratar la espasticidad muscular en pacientes con
esclerosis múltiple y lesiones de la médula espinal.
Debido a su especificidad como agonista de los receptores GABAB, en estudios
farmacológicos, ha evidenciado que estos receptores podrían estar implicados en la
etiología de algunos trastornos del SNC como la epilepsia, cognición, dolor, depresión,
reflujo gastroesofágico y adicción a drogas. Debido a esto, Baclofeno es considerado el
compuesto prototipo en el diseño de compuestos agonistas del receptor GABAB.
Capítulo 1. En este capítulo se presenta el diseño de nuevos análogos de Baclofeno.
X
Dada la importancia de los isoxazoles en química medicinal, se presenta el
diseño y síntesis de nuevos análogos de baclofeno en los cuales el átomo de nitrógeno
en posición forma parte de anillos de isoxazol y el anillo aromático en posición se
reemplazó con anillos aromáticos de clorotiofeno, clorofurano y fenilo como
bioisósteros.
Capítulo 2.
En este capítulo se describe y discute la síntesis de los análogos de baclofeno
previamente diseñados.
En la primera etapa, mediante una serie de reacciones que involucra una
reacción de Horner-Wadsworth-Emmons y adiciones de Michael, se llevó a cabo la
síntesis y separación de los nitrocompuestos, precursores clave para ensamblar los
anillos de isoxazol.
XI
En la segunda etapa, se efectúo la síntesis de los productos finales, mediante la
reacción clave, la cicloadición 1,3-dipolar alquino-óxido de nitrilo catalizada con Cu(I).
Los nitrocompuestos precursores se sometieron a una reacción de deshidratación, lo
cual permitió generar los óxidos de nitrilo, para ensamblar los anillos de isoxazol. Por
último, se efectuaron reacciones de hidrólisis básica, para obtener los productos finales
puros.ABSTRACT.
-Aminobutyric acid 1 (GABA) is the most important
inhibitory neurotransmitter in the central nervous system (CNS)
and exerts its physiological action through the interaction with
specific receptors, called GABAA, GABAB and GABAC.
Baclofen, a p-chlorophenyl GABA analog, is the only GABAB
receptor agonist ligand approved by the FDA to treat muscle
spasticity in patients with multiple sclerosis and spinal cord
injuries. Due to its specificity as a GABAB agonist in pharmacological studies, it has been
shown that these receptors are involved in the etiology of some CNS disorders such as
epilepsy, cognition, pain, depression, gastroesophageal reflux, and addiction to drugs.
Chapter 1.
In this chapter the design of new baclofen analogs is presented.
Given the importance of isoxazole rings in medicinal chemistry, the design and
synthesis of new baclofen analogs is presented, in which the nitrogen atom in -position
XIII
is included in isoxazole rings and the aromatic rings in position is
bioisosterically replaced with aromatic rings of chlorothiophene, chlorofuran and
phenyl.
Chapter 2.
This chapter describes and discusses the synthesis of the previously designed
Baclofen analogs.
In the first step, the synthesis and separation of the nitrocompounds (key
precursors in the synthesis of the isoxazole rings in the next step) was carried out
through a series of reaction that involve a Horner-Wadsworth-Emmons reaction and
nitromethane Michael additions.
XIV
In the second step, the synthesis of the final products was carried out. The key
reaction in this step was a Cu-catalyzed alkyne-nitrile oxide 1,3-dipolar cycloaddition
reaction. The precursor nitrocompounds were submitted to a dehydration reaction,
which allowed the generation in situ of the nitrile oxides in order to assemble the
isoxazole rings. Finally, basic hydrolysis reactions were carried out to generate the final
products
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
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
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
Author-wise bibliometric analysis based on entropy.
No full textAuthor-wise bibliometric analysis based on entropy.</p
Author Under Sail The Imagination of Jack London, 1893-1902
No full textIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Intro -- Title Page -- Copyright Page -- Dedication -- Contents -- Acknowledgments -- Introduction -- 1. Spirit Truth -- 2. From Absorption to Theatricality and Back Again -- 3. "I Will Build a New Present" -- 4. Sons as Authors -- 5. Fathers as Publishers -- 6. The Daughter as Author -- 7. Lovers as Authors -- 8. At Sea with the Family -- 9. Yellow News, Yellow Stories -- 10. The Return Home -- Notes -- Bibliography -- Index -- About Jay WilliamsIn Author Under Sail, Jay Williams offers the first complete literary biography of Jack London as a professional writer engaged in the labor of writing. It examines the authorial imagination in London's work, the use of imagination in both his fiction and nonfiction, and the ways he defined imagination in the creative process in his business dealings with his publishers, editors, and agents. In this first volume of a two-volume biography, Williams traverses the years 1893 to 1902, from London's "Story of a Typhoon" to The People of the Abyss. The Jack London who emerges in the pages of Author Under Sail is a writer whose partnership with publishers, most notably his productive alliance with George Brett of Macmillan, was one of the most formative in American literary history. London pioneered many author models during the heyday of realism and naturalism, blurring the boundaries of these popular genres by focusing on absorption and theatricality and the representation of the seen and unseen. London created an impassioned, sincere, and extremely personal realism unlike that of other American writers of the time. Author Under Sail is a literary tour de force that reveals the full range of London as writer, creative citizen, and entrepreneur at the same time it sheds light on the maverick side of machine-age literature.Description based on publisher supplied metadata and other sources.Electronic reproduction. Ann Arbor, Michigan : ProQuest Ebook Central, YYYY. Available via World Wide Web. Access may be limited to ProQuest Ebook Central affiliated libraries
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