1,923 research outputs found
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
Impact of Multiple Curve Dynamics in Credit Valuation Adjustments
No full textWe present a detailed analysis of interest rate derivatives valuation under
credit risk and collateral modeling. We show how the credit and collateral extended
valuation framework in Pallavicini et al (2011) can be helpful in defining the key
market rates underlying the multiple interest rate curves that characterize current
interest rate markets. We introduce the collateralized valuation measures and formulate
a consistent realistic dynamics for the rates emerging from our analysis. We
point out limitations of multiple curve models with deterministic basis considering
valuation of particularly sensitive products such as basis swaps
Public Sculptures of Petar Pallavicini in Dubrovnik
No full textPored niza poznatih skulptura, Petar Pallavicini je autor još dvaju skulptorskih djela u Dubrovniku. Godine 1935/6. izveo je reljefe za tri fasade Narodne banke u Dubrovniku. To su četiri reljefa smještena u zabate nad otvorima prizemlja Banke, alegorije tradicionalnih dubrovačkih gospodarskih grana. Nakon II. svjetskog rata, 1947/9. izrađuje reljef nadgrobnog spomenika grobnice obitelji Miljan na dubrovačkom groblju Boninovo.Born in Korčula, Petar Pallavicini (1887-1958) spent most of his life in Belgrade, where, attracted by the professional prospects of the then capital, he decided to settle in 1921 after graduating from the Art Academy in Prague. It was in Belgrade that he produced a series of decorative sculptures and works in the style he himself characterised as “spiritualised cubism”. In Dubrovnik, where he enjoyed most of his summers, Pallavicini was commissioned to execute the monument to Baltazar Bogišić, erected in Cavtat in 1913, where it still stands. Less known, however, is Pallavicini’s decorative work in Dubrovnik. The building of the National Bank was constructed in 1935/36 in one of the main thoroughfares of Dubrovnik (today Ulica hrvatskih branitelja). Pallavicini’s four reliefs, allegories of the traditional Dubrovnik crafts, adorn the pointed lunettes. The figures depicted in the relief panels are static, contemplative and lightly draped, the latter being his frequent expression. Morphological characteristics of the works and an article published in the paper “Novo doba” point to Petar Pallavicini as the author of this public relief in Dubrovnik. A reason more why these sculptures deserve our attention is the fact that in this period the sculpture of Dubrovnik was very modest.
Between 1947 and 1949 Pallavicini was commissioned to decorate a headstone at Boninovo—Dubrovnik cemetry. He is the author of a bronze relief on the family grave of his friend, painter Niko Miljan. The relief with a motif of the Virgin with the Child reflects intimism, its religious theme being rare in the post-war sculpture dominated by socialist realism
Heteroaryloxy analogues of WB4101: synthesis and biological evaluation at alpha1-adrenoreceptor subtypes
No full textThe physiological role of the three α1-adrenoreceptor (α1-AR) subtypes (α1A, α1B and α1D) has been intensively investigated in recent years as well as their involvement in pathological disorders, in particular in hypertension and in lower urinary tract symptoms (LUTS) secondary to benign prostatic hyperplasia (BPH).
Our research group has long been involved in designing new α1-AR ligands structurally related to 2-(2,6-dimethoxyphenoxy)ethylaminomethyl- 1 ,4-benzodioxane (WB4101), a potent α1 antagonist with a slight selectivity for α1A- and, to a minor extent, for α1D-ARs with respect to α1B-AR and 5-HT1A serotoninergic receptor. More recently, we have extensively investigated the role of the phenoxy moiety of WB4101 in the interaction with α1-AR subtypes and 5-HT1A receptor through a planned sequence of modifications of this molecule portion, consisting of combining a wide series of different ortho substituents or of introducing an additional or fused benzene or cyclohexane ring.1-4 The significant modulation of the affinity, activity and selectivity profile resulting form such modifications prompted us to design new WB4101 analogues, where the phenoxy moiety is b-fused to a saturated or unsaturated five-membered heterocycle, the heteroatom of the additional cycle replacing the oxygen of the removed methoxyl.
Here, we report the synthesis of 6-methoxydihydroindolyl-7-oxy, 6-methoxybenzofuran-7-oxy and 6-methoxydihydrobenzofuran-7-oxy analogues of WB4101, in both the enantiomeric forms, and discuss the results of the functional and binding studies at α1-AR subtypes and 5-HT1A receptor.
[1]Bolchi C. et al. Bioorg. Med. Chem. 2004, 12,4937-51.
[2]Fumagalli L. et al, Bioorg. Med. Chem. 2005, 13, 2547-59.
[3)Pallavicini M. et al Eur. J. Med. Chem. 2006, 4, 11025-40.
[4]Pallavicini M. et al. J Med. Chem. 2006, 4, 97140-9
Exploring the immune resilience of Mediterranean mussels: Recent advances and future directions
No full textThe Mediterranean mussel (Mytilus galloprovincialis) is a key species in European aquaculture, known for its economic and societal importance, particularly as a primary source of income for local fisheries in European coastal areas. While historically resilient to the mass mortality events that have affected other bivalve species, M. galloprovincialis may face increasing threats from emerging pathogens, including bacteria, viruses, and eukaryotic parasites. These microorganisms, often opportunistic, pose heightened risks in the current climate change scenario, where heatwaves are becoming increasingly frequent and the persistent presence of pollutants is suspected to impair the functional response of hemocytes. Over the past decade, significant advancements in immunological research have provided deeper insights into the cellular and molecular mechanisms underlying the robust defense system of M. galloprovincialis, which allows this species to efficiently cope with a broad range of infections. By analyzing the scientific literature published on mussel immunology over the past ten years, this review consolidates current knowledge on the immune system of the Mediterranean mussel. We place a particular focus on the cellular and molecular components involved in the recognition and elimination of microbial pathogens and discuss how the most recent discoveries may inform improved management and disease mitigation strategies for Mediterranean mussel farming in the in the years to come
Eosinofili, livelli sierici e rilascio in vitro di proteine cationiche eosinofiliche (ECP, EPX) in pazienti affetti da carcinoma renale in trattamento con interleuchina-2.
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Comparative genomics reveals 13 different isoforms of mytimycins (A-M) in mytilus galloprovincialis
No full textMytimycins are cysteine-rich antimicrobial peptides that show antifungal properties. These peptides are part of the immune network that constitutes the defense system of the Mediterranean mussel (Mytilus galloprovincialis). The immune system of mussels has been increasingly studied in the last decade due to its great efficiency, since these molluscs, particularly resistant to adverse conditions and pathogens, are present all over the world, being considered as an invasive species. The recent sequencing of the mussel genome has greatly simplified the genetic study of some of its immune genes. In the present work, we describe a total of 106 different mytimycin variants in 16 individual mussel genomes. The 13 highly supported mytimycin clusters (A–M) identified with phylogenetic inference were found to be subject to the presence/absence variation, a widespread phenomenon in mussels. We also identified a block of conserved residues evolving under purifying selection, which may indicate the “functional core” of the mature peptide, and a conserved set of 10 invariable plus 6 accessory cysteines which constitute a plastic disulfide array. Finally, we extended the taxonomic range of distribution of mytimycins among Mytilida, identifying novel sequences in M. coruscus, M. californianus, P. viridis, L. fortunei, M. philippinarum, M. modiolus, and P. purpuratus
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