1,721,108 research outputs found
Identification, pharmacological evaluation and binding mode analysis of novel chromene and chromane based σ1 receptor ligands
No full textA set of aminoethyl substituted chromenes 3 and chromanes 4, originally developed as antiprotozoal drugs was evaluated as novel types of σ1 receptor ligands. Analysis of SAR showed that chromenes 3 have a higher σ1 affinity than chromanes 4. A distance of four bond lengths between the basic amino moiety and the phenyl ring (3c), an alicyclic N-substituent such as the cyclohexylmethyl moiety (3l), and methylation of the secondary amine to afford a tertiary amine (3n) result in very high σ1 affinity and selectivity over the σ2 subtype. Compounds 3a-n and 4a-e were docked into the putative binding site of the σ1 receptor model and the relevant binding mode was analyzed and scored. Specifically, for the best σ1 ligand 3n, a salt bridge between Asp126 and the protonated amino group, an H-bond between the receptor backbone NH group (Ala122-Glu123) and the methoxy moiety of 3n, a lipophilic protein cavity encasing the chromene ring, and a T-shaped π-π stacking between the indole ring of Trp121 and the phenyl ring of 3n represent the most important ligand/protein stabilizing interactions. The binding pose of 3n was compared with the binding poses of the non-methylated chromene 3c, the saturated chromane 4c, and the N-cyclohexylmethyl derivative 3l. The contribution of the single amino acids to the overall free binding enthalpy was analyzed
Synthesis and pharmacological evaluation of enantiomerically pure endo-configured KOR agonists with 2-azabicyclo[3.2.1]octane scaffold
No full textConformationally restricted bicyclic KOR agonists 10 with an endo-configured amino moiety were synthesized
to analyze the bioactive conformation of conformationally flexible KOR agonists such as 2–5. A
seven-step synthesis starting with (S)-configured 4-oxopiperidine-2-carboxylate 13 was developed. cisand
trans-configured diesters 12 were obtained in a 3 : 1 ratio via hydrogenation of the α,β-unsaturated
ester 14. After establishment of the bicyclic scaffold, a diastereoselective reductive amination of ketone 11
provided exclusively the endo-configured bicyclic amines 10a,b. The 3 : 1 mixtures of enantiomers were
separated by chiral HPLC, respectively, leading to enantiomerically pure KOR agonists (1S,5S,7R)-10a,b
and (1R,5R,7S)-10a,b (ent-10a,b). The KOR affinity was determined in receptor binding studies with the
radioligand [3H]U-69 593. The high KOR affinity of endo-configured amines 10a (Ki = 7 nM) and 10b (Ki =
13 nM) indicates that the dihedral angle of the KOR pharmacophoric element N(pyrrolidine)–C–C–N
(phenylacetyl) of 42° is close to the bioactive conformation of more flexible KOR agonists. It should be
noted that changing the configuration of potent and selective KOR agonists 10a and 10b led to potent
and selective σ1 ligands (e.g. ent-10a Ki(σ1) = 10 nM)
Synthesis, pharmacological evaluation and σ1 receptor interaction analysis of hydroxyethyl substituted piperazines
No full textStarting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. σ receptor affinity was recorded using receptor material from both animal and human origin. σ1 affinities determined with guinea pig brain and human RPMI 8226 tumor cell lines differed slightly but showed the same tendency. (S)-2-[4-(Cyclohexylmethyl)-1-(naphthalene-2-ylmethyl)piperazin-2-yl]ethanol (7c) revealed the highest affinity at human σ1 receptors (Ki = 6.8 nM). The potent σ1 receptor ligand 7c was able to inhibit selectively the growth of three human tumor cell lines with IC50 values in the low micromolar range. The reduced growth of the RPMI-8226 cell line was caused by apoptosis. The interaction of 7c with the σ1 receptor was analyzed in detail using the 3D homology model of the σ1 receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human σ1 receptor
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe 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
Get PDF“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
Get PDFWe 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
Get PDFWe 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
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