160,984 research outputs found
Morphing of ibogaine: A successful attempt into the search for sigma-2 receptor ligands
No full textIbogaine is a psychoactive indole alkaloid with high affinity for several targets including the σ2 receptor. Indeed, extensive data support the involvement of the σ2 receptor in neurological disorders, including Alzheimer’s disease, schizophrenia, alcohol abuse and pain. Due to its serious side effects which prevent ibogaine from potential clinical applications, novel ibogaine derivatives endowed with improved σ2 receptor affinity may be particularly beneficial. With the purpose to facilitate the investigation of iboga alkaloid derivatives which may serve as templates for the design of selective σ2 receptor ligands, here we report a deconstruction study on the ibogaine tricyclic moiety and a successive scaffold-hopping of the indole counterpart. A 3D-QSAR model has been applied to predict the σ2 pKi values of the new compounds, whereas a molecular docking study conducted upon the σ2 receptor built by homology modeling was used to further validate the best-scored molecules. We eventually evaluated pinoline, a carboline derivative, for σ2 receptor affinity through radioligand binding assay and the results confirmed the predicted high μM range of affinity and good selectivity. The obtained results could be helpful in the drug design process of new ibogaine simplified analogs with improved σ2 receptor binding capabilities
Variations on the Author
No full text“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
Synthesis and pharmacological evaluation of 1-benzylpiperazine and 4-benzylpiperidine as potent sigma ligands.
No full textIt is now well established that sigma receptors are an independent class of receptors expressed in peripheral organs and in the central nervous system. There are at least two identified subtypes, namely sigma1 and sigma2, with distinct functional roles and different pharmacological characteristics. On the basis of their neuroregulative and neuropotective functions sigma1 agents could be potentially used for the treatment of depression and psychiatric disorders. The finding of high concentration of sigma2 receptors in neuronal and non-neuronal tumor cell lines provides evidence of a possible role in anticancer therapy. A variety of chemically unrelated compounds is able to bind sigma receptors, however only few bind with high affinity and selectivity to sigma receptor subtypes. This situation has given new impulse to medicinal chemists for the search of new and more selective ligands.We have recently reported that substituted 1-benzylpiperazine and 4-benzylpiperidine derivatives were shown to be high-affinity sigma ligands (Ki in the nanomolar range) with a slight preference for sigma1 over sigma2 receptors1-2. With the aim to improve sigma1/sigma2 selectivity we have studied the effect of some substitutions of the oxygen atoms on the 1,3-dioxolane ring by synthesizing 1,3-oxathiolane, 1,3-dithiolane, tetrahydro-furan, cyclopentanone and cyclopentanol derivatives as depicted below. A spiro derivative was additionally prepared and tested to study the influence of the two aromatic rings on receptor affinity. The preliminary pharmacological results show a significant improvement of sigma1 selectivity for compound A. Structure-activity relationship will be extensively discussed during the congress
CCB: A novel anologue of MPCB with high binding affinity and specific kappa opioid receptor agonist
No full textnot availabl
Repurposing of Human Kinase Inhibitors in Neglected Protozoan Diseases
No full textHuman African trypanosomiasis (HAT), Chagas disease, and leishmaniasis belong to a group of infectious diseases known as neglected tropical diseases and are induced by infection with protozoan parasites named trypanosomatids. Drugs in current use have several limitations, and therefore new candidate drugs are required. The majority of current therapeutic trypanosomatid targets are enzymes or cell-surface receptors. Among these, eukaryotic protein kinases are a major group of protein targets whose modulation may be beneficial for the treatment of neglected tropical protozoan diseases. This review summarizes the finding of new hit compounds for neglected tropical protozoan diseases, by repurposing known human kinase inhibitors on trypanosomatids. Kinase inhibitors are grouped by human kinase family and discussed according to the screening (target-based or phenotypic) reported for these compounds on trypanosomatids. This collection aims to provide insight into repurposed human kinase inhibitors and their importance in the development of new chemical entities with potential beneficial effects on the diseases caused by trypanosomatids
Anti-amnesic and neuroprotective actions of the sigma-1 receptor agonist (-)-MR22 in rats with selective cholinergic lesion and amyloid infusion
No full textanti-amnesic properties of (±)-PPCC, a novel sigma receptor ligand, on cognitive dysfunction induced by selective cholinergic lesion in rats
No full textGoing Beyond Counting First Authors in Author Co-citation Analysis
No full textThe 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
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