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Iperoxo/dequalinium and W84/dequalinium hybrid ligands: synthesis, pharmacological and computational investigation at M2 mAChRs
No full text[PO 032] The use of bitopic ligands to study the properties of Muscarinic Acetylcholine Receptors (mAChRs) is a very active field of research [1,2,3]. In this regard, bipharmacophoric molecular probes were found to switch between two different binding orientations in the M2 subtype, resulting in both active and inactive populations of receptors bound by a given ligand, a behavior that has been termed dynamic ligand binding [2]. Continuing our interest in this field, we focused our attention on the properties of Dequalinium chloride, a bis-pyridinium quaternary ammonium compound, which was recently reported to act as a potent muscarinic allosteric modulator, showing an overall selectivity towards the M2 subtype [4]. Starting from this observation, we designed and synthesized two series of novel hybrid ligands incorporating in their molecular skeleton the allosteric moiety of Dequalinium (Figure 1). The first series is based on the combination of Dequalinium with the orthosteric superagonist Iperoxo and aimed at novel chemical probes interacting cooperatively with both the orthosteric and the allosteric binding site. In the second series, Dequalinium was hybridized with the allosteric modulator W-84, affording new putative allo/allosteric ligands. In this study, the newly synthetized compounds have been characterized through competitive binding assays at the five mAChR subtypes. The activity on the allosteric site has been investigated by measuring the affinity (logKocc) at the [3H]-NMS-occupied muscarinic hM2 subtype. Moreover, docking simulations have been performed to highlight the interactions within the ortho/allosteric binding pockets of the hM2 crystal structure addressing the role of linker length. The synthetic approach and the details of the pharmacological and computational investigations will be illustrated and discussed.
References
1. Holze, J.; Bermudez, M.; Pfeil, E.M.; Matera, C.; Dallanoce, C.; De Amici, M. et al. ACS Pharmacol. Transl. Sci. 2020, 3, 859–867.
2. Bock, A.; Bermudez, M.; Krebs, F.; Matera, C.; Chirinda, B.; Sydow, D.; Dallanoce, C. et al. J. Biol. Chem. 2016, 291, 16375.
3. Bock, A.; Merten, N.; Schrage, R.; Dallanoce C.; Bätz J.; Klöckner J.; Schmitz J.; Matera C. et al. Nat. Commun. 2012, 2, 1044.
4. Mazzolari, A.; Gervasoni, S.; Pedretti, A.; Fumagalli, L.; Matucci, R.; Vistoli, G. Int. J. Mol. Sci. 2020, 21, 5961
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
Cholinergic receptors contribute to maintain the quiescent status of adipose mesenchymal stem cells
No full textMesenchymal stem cells (MSCs), also known as stromal mesenchymal stem cells, are multipotent cells, which can be found in many tissues and organs as bone marrow and adipose tissue. In particular MSCs derived from Adipose tissue (ASCs) are an attractive cell source for regenerative medicine. Acetylcholine (ACh), the most important neurotransmitter in Central (CNS) and peripheral nervous system (PNS), plays a key roles also in non-neural tissue. Although MSCs express cholinergic receptors, their role has been poorly investigated. Analysis by RT-PCR have demonstrated that ASCs express several muscarinic and nicotinic receptor subtypes. In particular M2 mAChR and alpha7 nAChR expression was also confirmed by western blot analysis. In present work cholinergic effects were studied on rat ASCs. By MTT and FACS analysis we have demonstrated that M2 receptor activation caused a reversible reduction of cell proliferation. Moreover, by wound healing and transwell assays, we have also demonstrated that M2 receptors caused an inhibition of cell migration, indicating the ACh as possible modulator of ASCs proliferation and migration. Similarly to that observed for M2 receptor, preliminary data on α-7 nAChR demonstrate that this receptor is able to modulate cell proliferation and migration. Interestingly the activation of α-7 nAChR appears also up-regulate the expression of M2 receptor, suggesting a feedback positive loop between the muscarinic and nicotinic receptors. Our results indicate that ACh via M2 mAChR and α-7 nAChR, may contribute to the maintaining of the ASCs quiescent status. These data are the first evidence that ACh, might contribute to control ASCs physiology
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
Novel oxotremorine-related heterocyclic derivatives: Synthesis and in vitro pharmacology at the muscarinic receptor subtypes.
No full textPharmacological profile of enantiomerically pure chiral muscarinic agonists - desoxymuscarines
No full textA chemoenzymatic approach to the synthesis of the stereoisomers of a b-adrenergic receptor antagonist.
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