Synthesis and binding affinity of new 1,4-disubstituted triazoles as potential dopamine D(3) receptor ligands.

A series of new 1,4-disubstituted triazoles was prepared from appropriate arylacetylenes and aminoalkylazides using click chemistry methodology. These compounds were evaluated as potential ligands on several subtypes of dopamine receptors in in vitro competition assays, showing high affinity for dopamine D3 receptors, lower affinity for D2 and D4, and no affinity for the D1 receptors. Compound 18 displayed the highest affinity at the D3 receptor with a Ki value of 2.7 nM, selectivity over D2 (70-fold) and D4 (200-fold), and behaviour as a competitive antagonist in the low nanomolar range.

Novel antiobesity agents: synthesis and pharmacological evaluation of analogues of Rimonabant and of LH21.

Searching for novel antiobesity agents, a series of cannabinoid LH21 and of Rimonabant-fatty acid amide analogues have been prepared. Synthesis of pyrazoles 2a-2c was achieved by a two steps simple methodology via α,ß-unsaturated ketones. Carboxamides 8a-8h were obtained in good yields from esters 7a-7c by a one-pot procedure which takes place under mild conditions. New compounds have been evaluated in vivo as anorectic agents. Some of them showed interesting properties reducing food intake in rats by a mechanism which does not involve the endocannabinoid system.

The structure of Rimonabant in the solid state and in solution: an experimental and theoretical study.

The X-ray molecular structure of Rimonabant methanol solvate has been determined together with the (1)H, (13)C and (15)N NMR spectra in acetone solution. B3YP/6-311++G(d,p) calculations have been performed out to determine two minimum energy conformations, on these geometries GIAO calculations were carried out to obtain the corresponding absolute shieldings that were compared with the experimental chemical shifts.

Antiobesity designed multiple ligands: Synthesis of pyrazole fatty acid amides and evaluation as hypophagic agents.

Searching for new antiobesity agents, a new series of fatty acid amide derivatives of 1,5-diarylpyrazole have been synthesized as dual peroxisome proliferator activated receptor alpha (PPARalpha)/cannabinoid receptor ligands. The compounds have been evaluated in vivo and in vitro as PPARalpha activators and as cannabinoids in two tests of the mouse tetrad. In vivo, food intake studies have been performed with all the compounds. No significant cannabinoid activity has been found but some compounds behaved as potent PPARalpha activators. Several compounds showed anorexigenic properties reducing food intake in rats.

Multistructure 3D-QSAR studies on a series of conformationally constrained butyrophenones docked into a new homology model of the 5-HT2A receptor.

The present study is part of a long-term research project aiming to gain insight into the mechanism of action of atypical antipsychotics. Here we describe a 3D-QSAR study carried out on a series of butyrophenones with affinity for the serotonin-2A receptor, aligned by docking into the binding site of a receptor model. The series studied has two peculiarities: (i) all the compounds have a chiral center and can be represented by two enantiomeric structures, and (ii) many of the structures can bind the receptor in two alternative orientations, posing the problem of how to select a single representative structure for every compound. We have used an original solution consisting of the simultaneous use of multiple structures, representing different configurations, binding conformations, and positions. The final model showed good statistical quality (n = 426, r2 = 0.84, q2LOO = 0.81) and its interpretation provided useful information, not obtainable from the simple inspection of the ligand-receptor complexes.

Synthesis and biological evaluation of new quinazoline and cinnoline derivatives as potential atypical antipsychotics.

Four new diaza analogues (14, 15, 23, and 24) of the conformationally constrained aminobutyrophenone derivatives QF0104B (5) and QF0108B (6) were synthesized (Schemes 2 and 3), and evaluated for their binding affinities (Table) towards the serotonin 5-HT2A and 5-HT2C, and the dopamine D2 receptors. Among the new compounds, the quinazoline derivative 15 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydroquinazolin-5-one) exhibited the highest affinities towards the serotonin 5-HT2A and dopamine D2 receptors, and it is in the borderline of potential atypical antipsychotics. The cinnoline derivative 23 (= 7-{[4-(4-fluorobenzoyl)piperidin-1-yl]methyl}-5,6,7,8-tetrahydro-3-methylcinnolin-5-one) displayed high selectivity in its binding profile towards the 5-HT2C compared to both the 5-HT2A and D2 receptors.

Synthesis and binding affinity of novel 3-aminoethyl-1-tetralones, potential atypical antipsychotics.

A series of 3-aminoethyl-1-tetralones, conformationally constrained higher homologues of haloperidol (standard for typical antipsychotic profile), have been obtained by a four-step route from valerolactone. Their binding affinities at dopamine D(2) and serotonin 5-HT2A and 5-HT2C receptors were determined, showing in some cases an atypical antipsychotic profile.

Switching of PET fluorescence signals induced by ligand exchange reactions of N-(9-anthrylmethyl)amine on Cu(II) complexes and its application to postcolumn detection of glyphosate.

N-(9-Anthrylmethyl)amines which combine a fluorescent subunit and a chelate forming fragment have revealed a signal switching property in an aqueous solution upon complexation (off) with Cu(II) and liberation (on) of the probe molecule by substitution with an other ligand. The ligand exchange reaction between N-(phosphonomethyl)glycine (glyphosate), a typical herbicide, with N-(9-anthrylmethyl)amines on Cu(II) ion leads the fluorescence signal intensity to revive, providing an indirect detection system of glyphosate available in water of neutral pH region. The present system has been applied to the post column detection in the ion chromatographic separation of glyphosate and its metabolite aminomethylphosphonic acid (AMPA).

The shifting balance of littoral predator-prey interaction in regimes of hydrodynamic stress.

Above lowshore levels of wave-beaten rocky shores, desiccation from tidal exposure and hydrodynamics stresses from wave action are thought to create refuges from predation, allowing concentrations of sedentary prey such as mussel beds. Underwater time-lapse photography on rocky shores in Southern California revealed that dense aggregations of spiny lobsters prey on mussels during nocturnal high tides. In contradiction of the refuge hypothesis, the densest aggregations occurred on midshore levels of the most wave-exposed site, a semi-protected site showed intermediate densities, and a protected site showed only sparse numbers of lobsters. On wave-beaten shores, the lobsters' high mobility and rapid prey handling allowed them to exploit intertidal prey in the brief period at extreme high tide, when both desiccation and hydrodynamic stresses were at a minimum. The spatial differences in lobster densities were, however, positively related to the recruitment rates of juvenile mussels, the preferred prey. A field experiment demonstrated that predation by lobsters within a mussel bed affects the age/size structure of the bed without changing primary percent coverage. Therefore, concentrations of adult prey on some wave-swept sites appear to result from elevated rates of prey recruitment that surpass rates of predation, rather than absolute refuges from predation.

Hidrops Fetal no Inmune

Se revisan los aspectos generales de la etiología, fisiopatología, diagnóstico y manejo del Hidrops Fetal no Inmune para que durante el control prenatal, con un mejor conocimiento de esta entidad, se considere como posibilidad diagnóstica, y permita la realización de nuevos estudios sobre incidencia, etiología y manejo en nuestro medio