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ANALOGHI STRUTTURALI DEL WB 4101: PROGETTAZIONE, SINTESI E VALUTAZIONE BIOLOGICA
No full textI recettori a1-adrenergici appartengono alla vasta famiglia dei recettori transmembranali accoppiati a proteine G e comprendono tre sottotipi (a1A, a1B e a1D)1,2 dei quali si conoscono sia i profili farmacologici sia i geni codificanti. Il crescente interesse verso lo studio di ligandi selettivi per tali sottotipi è da ricondurre alle potenzialità terapeutiche di antagonisti specifici per i sottotipi a1A e a1D nel trattamento di disturbi del basso tratto urinario3. E’ noto, infatti, che gli a1A antagonisti sono utili nel trattamento dell’ipertrofia prostatica benigna così come gli antagonisti a1D alleviano i sintomi irritativi ad essa correlati, essendo tali sottotipi recettoriali presenti, rispettivamente, nella prostata4 e nella vescica3,5. Il primo antagonista a1, il WB-41016, risale agli anni ’70 e presenta una struttura aminometil-1,4-benzodiossanica; successivamente, si è scoperto che questo antagonista è selettivo per i sottotipi a1A e a1D rispetto al sottotipo a1B e al recettore serotoninergico 5-HT1A7,8.
La progettazione di ligandi selettivi per i tre sottotipi si basa sull’utilizzo di modelli farmacoforici9,10, ottenuti da classi eterogenee di composti selettivi, sugli studi di docking, che si avvalgono di templati della rodopsina11, e sulla conoscenza, acquisita attraverso esperimenti di mutagenesi12, dei siti di legame coinvolti nell’interazione ligando-recettore.
Sulla base dei risultati delle suddette ricerche abbiamo intrapreso uno studio relativo ad analoghi strutturali del WB 4101 al fine di identificare i requisiti strutturali necessari per ottenere ligandi ad alta affinità per il sottotitpo a1A e con buona selettività rispetto agli altri sottotipi a1 e al recettore serotoninergico 5-HT1A. Sono state quindi progettate le seguenti modifiche: sostituzione del benzodiossano con naftodiossano o tetraidronafttodiossano; introduzione di un atomo di cloro o di un gruppo acetilico in posizione 8 del benzodiossano; sostituzione della porzione 2,6-dimetossifenilica con 4- o 5-fenil-2-metossifenile, 2-cloro-6-metossifenile, 2-metossi-naftile o 2-metossitetraidronaftile.
Di tutti i composti compreso il WB 4101, sono stati sintetizzati e valutati biologicamente entrambe gli enantiomeri.
Bibliografia
1. (a) Ford, A. P. D. W.; Williams, T. J.; Blue, D. R.; Clarke, D. E. Trends Pharmacol. Sci. 1994, 15, 167. (b) Hieble, J. P.; Ruffolo, R. R., Jr. Prog. Drug Res. 1996, 47, 81.
2. Faure, C.; Pimoule, C.; Arbilla, S.; Langer, S. Z.; Graham, D. Eur. J. Pharmacol. Mol. Pharmacol. 1994, 15, 167.
3. Malloy, B. J.;Price, D.T.; Price, R. R.; Bienstock, a. M.; Dole, M. K.; Funk, B. L.; Rudner, X. L.; Richardson, C. D.; Donatucci, C. F.; Schwinn, D. A. J. Urol. 1998, 160, 937.
4. Price, D. T.; Schwinn, D. A.; Lomasney, J. W.; Allen, L. F.; Caron, M. G.; Lefkowitz, R. J. J. Urol. 1993, 250, 546.
5. Schwinn, D. A.; Michelotti, G. A. BJU International 2000, 2, 6.
6. Kenny, B.; Ballard, S.; Blagg, J.; Fox, D. J. Med. Chem. 1997, 40, 1293.
7. Nelson, W. L. ; Wennerstrom, J. E.; Dyer D. C. J. Med. Chem. 1977, 20, 880.
8. Ruffolo, R. R. Jr.; Stadel, J. M.; Hieble, J. P. Med. Res. Rev. 1994, 14, 229.
9. Barbaro, R.; Betti, L.; Botta, M.;Corelli, F.; Giannaccini, G.; Maccari, L.; Manetti, F.; Strappaghetti, G.; Corsano, S. Bioorg. Med. Chem. 2002, 10, 361.
10. Bremner, J. B.; Coban, B.; Griffith, R. ; Groenewoud, K. M.; Yates, B. F. Bioorg. Med. Chem. 2000, 8, 201.
11. Leonardi, A.; Barlocco, D.; Montesano, F.; Cignarella, G.; Motta, G.; Testa, R.; Poggesi, E.; Seeber, M.; De Benedetti, P. G.; Fanelli, F. J. Med. Chem. 2004, 47, 1900.
12. Piascik, M. T.; Perez, D. J. Pharmacol. Exp. Ther. 2001, 298, 403
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
Synthesis and a4b2 nicotinic affinity of the stereoisomers of 2-(1-methyl-2-pyrrolidinyl)-1,4-benzodioxane and of its nor-methyl derivative
No full textNeuronal nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels, composed of five subunits forming a pore. The variety of receptor subtypes is mainly due to the diversity of a and b subunits encoded by at least 12 different genes (a2-10, b2-b4). These receptors play an important role in the neurotransmission in the CNS and their dysfunction has been related to a number of severe brain pathologies, including Parkinson’s and Alzheimer’s diseases, schizophrenia, anxiety and some form of epilepsy. As a result novel ligands for neuronal nAchRs, in particular for the two major a4b2 and a7 brain subtypes, may have a great potential as pharmaceutical aiming at several neurological disorders. Nicotine, the prototype of nicotinic agonists, has inspired the design of novel nicotinoids, mainly differing by the nature of the hydrogen bond acceptor and p-electron rich group (HBA/p), which is a 3-pyridinil in nicotine, and/or by conformational flexibility.Recently, we have reported the synthesis and the binding affinity, for a4b2 and a7 nicotinic subtypes, of the RS and SR enantiomers of 1,4-benzodioxane bearing a 1-methyl-2-pyrrolidinyl substituent at the 2-position (1).1 The designed structure, which can be seen as a rigidified analogue of nicotinic ligands such as prolinol phenyl ethers, is characterized by the presence of two vicinal stereocentres. These are connected by the sole bond, whose rotation is relevant to molecule conformation, and are placed in proximity of the critical cationic head with important consequences on the mutual disposition of N+ and HBA/p. Prompted by the finding that one of the two benzodioxane stereoisomers binds at a4b2 nicotinic receptor with submicromolar affinity, we designed a new synthesis, which allowed all the four stereoisomers of 1 to be obtained from (R)- and (S)-proline. Furthermore, the corresponding nor-methyl derivatives (2) were prepared
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
SEARCH FOR SELECTIVE ANTAGONISTS AT α1-ADRENORECEPTOR SUBTYPES: WB-4101 RELATED COMPOUNDS
No full textThe development of subtype selective α1 ligands is intensively pursued in order to obtain more effective and safer agents for the treatment of cardiovascular pathologies such as hypertension and arrhythmia, but also and particularly of benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS).
One of the oldest and most potent α1 antagonists is represented by WB-4101, a 2-aminomethyl-1,4-benzodioxane derivative which is slightly selective for α1A and, to a minor extent, for α1D-ARs with respect to α1B-AR and 5-HT1A serotoninergic receptor. Many structural modifications of WB-4101 have been done to improve both affinity and selectivity.1-4 Some evidences, resulting from mutagenesis and docking studies, suggest that the benzodioxane moiety and the 2,6-dimethoxyphenoxy residue of WB-4101 are, respectively, involved in conferring α1a selectivity and high α1 affinity. Consistently with these findings, our recent researches have demonstrated that removal of one or both ortho-methoxy substituents adversely affects the affinity for the three α1-AR subtypes, but not that for the 5-HT1A receptor.3
On the basis of these indications, we synthesized a number of S and R analogues of WB-4101, characterized by different substitutions at the benzodioxane and/or phenoxy fragment, in order to modulate and, hopefully, to improve the activity and selectivity profile of the parent compound. In particular, we considered derivatives with benzodioxane 8-substituted with F,4 Cl, OH or OMe 4 or fused with a cyclohexane to give a tetrahydronaphthodioxane polycycle.2 On the other hand, 2,6-dimethoxyphenyl residue was replaced by ortho methoxy substituted 1-naphthyl 2 or biphenyl systems. Finally, hybrid structures were designed combining some of the above modifications. After binding assays, which demonstrated the better α1a, α1b, α1d and 5-HT1A affinity of the S enantiomers, these latter were tested in functional assays on isolated tissues, finding that almost all were able to discriminate among the α1-AR subtypes.
1. Bolognesi M.L., Budriesi R., Cavalli A., Chiarini A., Gotti R., Leonardi A., Minarini A., Poggesi E., Recanatini M., Rosini M., Tumiatti V., Melchiorre C. J.Med.Chem. 1999, 42, 4214-4224.
2. Bolchi C., Catalano P., Fumagalli L., Gobbi M., Pallavicini M., Pedretti A., Villa L., Vistoli G., Valoti E. Bioorg.Med.Chem. 2004, 12, 4937-51.
3. Fumagalli L., Bolchi C., Colleoni S., Gobbi M., Moroni B., Pallavicini M., Pedretti A., Villa L., Vistoli G., Valoti E. Bioorg.Med.Chem. 2005, 13, 2547-2559.
4. Valoti E., Pallavicini M., Villa L., Pezzetta D. J.Org.Chem. 2001, 66, 1018-1025
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
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