Design, synthesis, and SAR analysis of novel selective sigma1 ligands.

A new series of arylalkyl- and alkenylamines was designed, synthesized, and evaluated for binding to sigma(1) and sigma(2) receptors. Many compounds exhibited nanomolar affinity for sigma(1) subtype receptor with good selectivity over sigma(2). A molecular modeling study was conducted in order to rationalize the experimental data, and the structure-receptor affinities are discussed.

Highly diastereoselective synthesis of enantiopure naphthylaminoalcohols with analgesic properties.

The diastereoselective synthesis via Grignard reaction of enantiopure analgesic naphthylaminoalcohols has been performed. The chiral racemic key intermediate 3-dimethylamino-2-methyl-1-(naphthalen-2-yl)propan-1-one and enantiomers were prepared and transformed into the desired compounds by addition of the organometallic reagent. The chemical characterization of all diastereoisomers was accomplished by 1H NMR and HPLC analyses and the absolute configuration assigned by CD spectroscopy. The in vitro and in vivo profile has also been evaluated.

Chiral arylpyrrolidinols: preparation and biological profile.

The preparation and biological evaluation of a new class of arylpyrrolidinols is reported. The antinociceptive activity was evaluated in vivo with the hot plate test (HPT) and formalin test (FT), excluding any involvement on motor coordination with the rota-rod test (RRT). The nociceptive behavior in the late phase of FT (representative of chronic pain) suggests an involvement of the antiinflammatory process and it is clearly influenced by the stereochemical features, being the eutomer of phenylpyrrolidinols, the (2R,3S) enantiomer. Despite this, a specific mechanism of action is not yet clarified.

Qualitative and quantitative structure-property relationships analysis of multicomponent potential bioglasses.

The results of a qualitative and quantitative structure-property relationships analysis of multicomponent potential bioglasses of composition (2 - y) SiO2 x 1 Na2O x 1.1 CaO x y P2O5 x x ZnO (x = 0, 0.16, 0.35, 0.78 and y = 0.10, 0.20, 0.36) are presented. Quantitative models are obtained by means of structural descriptors derived by molecular dynamics simulations and experimental data measured for density, thermal analysis, 29Si and 31P magic angle spinning NMR, and chemical durability in water. Analysis of the crystal species obtained upon glass crystallization helped in the rationalization of the structural role of the different components. Finally, glass surface characterization with scanning electron microscopy, transmission electron microscopy, and X-ray diffraction after soaking in acellular simulated body fluid demonstrated the in vitro bioactivity of the newly obtained 1.80 SiO2 x 1 Na2O x 1.1 Ca x 0.20 P2O5 x 0.16 ZnO (HP5Z5) glass, corresponding to x = 0.16 and y = 0.20.

Structure/transport relationships in silver-based oxide glasses: 1-D and 2-D NMR information.

AgI-doped silver oxide glasses are of interest both for their possible applications in electrochemical devices, and as a model system to study the transport/structure relationships in ionic glasses. Here we summarize the information given by 1-D and 2-D solid-state NMR measurements on both the cations dynamics and short (and medium) range structure of several glassy systems. Emphasis is given to understand how AgI enters into the glass matrix. A new and careful analysis of our previously reported 109Ag 1-D data shows that the glass matrix plays a relevant role in determining the efficiency of carriers formation, as well as their mobility. Finally, as an example of a modern 2-D NMR application to these materials, we report the first 11B and 17O Multiple Quantum MAS study on a glass of the system AgI:Ag2O:2B2O2, which confirms the nearly complete absence of non-bridging oxygens (NBOs) in the silver diborate composition.

Synthesis and pharmacological evaluation of new N-methyl-arylpyrrolidinols with analgesic activity.

In the present paper, we report on the synthesis and antinociceptive activity of a new series of N-methyl-arylpyrrolidinols that we designed for a rational structure-activity relationship (SAR) study. The antinociceptive properties were investigated in vivo by the hot plate and formalin tests in mice and control on the locomotory activity was also monitored by the rota rod test. With this aim, the evaluation of the lipophilicity of all compounds was performed by the Daylight computational method in order to better understand the SAR. Interesting properties were proven for the compounds of the entire series.

Application of 1H and 23Na magic angle spinning NMR spectroscopy to define the HRBC up-taking of MRI contrast agents.

The up-take of Gd(III) complexes of BOPTA, DTPA, DOTA, EDTP, HPDO3A, and DOTP in HRBC has been evaluated by measuring the lanthanide induced shift (LIS) produced by the corresponding dysprosium complexes (DC) on the MAS-NMR resonances of water protons and free sodium ions. These complexes are important in their use as MRI contrast agents (MRI-CA) in diagnostics. 1H and 23Na MAS-NMR spectra of HRBC suspension, collected at 9.395T, show only one signal due to extra- and intra-cellular water (or sodium). In MAS spectra, the presence of DC in a cellular compartment produces the LIS of only the nuclei (water proton or sodium) in that cellular compartment and this LIS can be related to the DC concentrations (by the experimental curves of LIS vs. DC concentrations) collected in the physiological solution. To obtain correct results about LIS, the use of MAS technique is mandatory, because it guarantees the only the nuclei staying in the same cellular compartment where the LC is present show the LIS. In all the cases considered, the addition of the DC to HRBC (100% hematocrit) produced a shift of only the extra-cellular water (or sodium) signal and the gradient of concentration (GC) between extra- and intra-cellular compartments resulted greater than 100:1, when calculated by means of sodium signals. These high values of GC are direct proofs that none of the tested dysprosium complexes crosses the HRBC membrane. Since the DC are iso-structural to the gadolinium complexes the corresponding gadolinium ones (MRI-CA) do not cross the HRBC membrane and, consequently, they are not up-taken in HRBC. The GC values calculated by means of water proton signals resulted much lower than those obtained by sodium signals. This proves that the choice of the isotope is a crucial step in order to use this method in the best way. In fact, GC value depends on the lowest detectable LIS which, in turn, depends on the nature of the LC (lanthanide complex) and the observed isotopes.

Regioselective enzymatic hydrolysis of acetylated pyranoses and pyranosides using immobilised lipases. An easy chemoenzymatic synthesis of alpha- and beta-D-glucopyranose acetates bearing a free secondary C-4 hydroxyl group.

Protected sugars with only one free hydroxyl group are useful building blocks for the synthesis of a large number of glycoderivatives. In order to avoid the problems of the classical chemical synthesis, we studied the regioselective enzymatic hydrolysis of different fully acetylated glycopyranoses and glycopyranosides. The main challenge was to obtain the hydrolysis of the substrates in only one position, with high regioselectivity, while avoiding any further hydrolysis towards partially acetylated sugars. Candida rugosa (CRL) and Pseudomonas fluorescens (PFL) lipases (EC 3.1.1.3) immobilised on octyl agarose afforded regioselective hydrolysis only in the 6- and 1-positions, respectively. Furthermore, a new one-pot chemoenzymatic approach has been developed in order to obtain alpha- and beta-protected glucopyranoses bearing a free secondary C-4 hydroxyl group. For instance, 1,2,3,6-tetra-O-acetyl-alpha-D-glucopyranose was easily synthesised in good overall yield (70%) starting from 1,2,3,4,6-penta-O-acetyl-alpha-D-glucopyranose by regioselective enzymatic hydrolysis in the 6-position, catalysed by CRL, followed by a temperature- and pH-controlled acyl migration.

Metal-induced assembling/disassembling of fluorescent naphthalenediimide derivatives signalled by excimer emission.

The new quadridentate bischelating ligands 2 and 3 display in solution the typical absorption and emission properties expected for naphthalenediimide derivatives. Spectrophotometric studies show that systems 2 and 3 interact with Zn(II), Cd(II) and Cu(I) in CHCl3 or MeCN according to an apparent 1:1 stoichiometry. Molecular modelling, ESI-MS and 1H NMR experiments indicate that the complex species formed in the presence of stoichiometric amounts of metal ion are nonhelical [2 + 2] adducts. The metal-induced self-assembling process is signalled by an intense excimer-type emission caused by the intramolecular interaction of two naphthalenediimide subunits that face each other in the [2 + 2] adduct, as shown by molecular modelling studies. In the presence of excess metal ion, a disassembling process takes place, leading to a dinuclear complex with a 2:1 metal/ligand stoichiometry, in which the intramolecular excimer is no longer allowed to form because the interaction between the naphthalenediimide subunits has been lost. Thus, the overall metal-induced assembling/disassembling process is signalled by the appearance and disappearance of the excimer band in the emission spectrum.