RESUMO
Two isomers of the hexahydro-tetraazaacenaphthylene templates (1 and 2) are presented as novel, potent, and selective corticotropin releasing factor-1 (CRF1) receptor antagonists. In this paper, we report the affinity and SAR of a series of compounds, as well as pharmacokinetic characterization of a chosen set. The anxiolitic activity of a selected example (2ba) in the rat pup vocalization model is also presented.
Assuntos
Acenaftenos/farmacologia , Acenaftenos/uso terapêutico , Ansiedade/tratamento farmacológico , Depressão/tratamento farmacológico , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Acenaftenos/síntese química , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Estrutura Molecular , Ratos , Ratos Wistar , Relação Estrutura-AtividadeRESUMO
The practical, stereoselective synthesis of the three diastereoisomeric 1,2-trans-dicarboxy-4,5-cyclohexanediols 1-3 (DCCHDs) is described, starting from a common precursor, easily available in both enantiomeric forms. The regioselective derivatization of all functional groups of 1 is also reported. The three DCCHDs are locked in a single chair conformation and thus can be used to mimic vicinally disubstituted monosaccharides of any relative configuration.
Assuntos
Cicloexanóis/química , Cicloexanóis/síntese química , Mimetismo Molecular , Monossacarídeos/química , Monossacarídeos/síntese química , Desenho de Fármacos , Conformação MolecularRESUMO
We determined the structure of the hydrated Cu(II) complex by both neutron diffraction and first-principles molecular dynamics. In contrast with the generally accepted picture, which assumes an octahedrally solvated Cu(II) ion, our experimental and theoretical results favor fivefold coordination. The simulation reveals that the solvated complex undergoes frequent transformations between square pyramidal and trigonal bipyramidal configurations. We argue that this picture is also consistent with experimental data obtained previously by visible near-infrared absorption, x-ray absorption near-edge structure, and nuclear magnetic resonance methods. The preference of the Cu(II) ion for fivefold instead of sixfold coordination, which occurs for other cations of comparable charge and size, results from a Jahn-Teller destabilization of the octahedral complex.
RESUMO
Using a first-principles approach, we characterize dangling bond defects at Si-SiO2 interfaces by calculating hyperfine parameters for several relaxed structures. Interface models, in which defect Si atoms remain close to crystalline sites of the substrate upon relaxation, successfully describe P(b) and P(b0) defects at (111) and (100) interfaces, respectively. On the basis of calculated hyperfine parameters, we discard models of the P(b1) defect containing a first neighbor shell with an O atom or a strained bond. A novel model consisting of an asymmetrically oxidized dimer yields hyperfine parameters in excellent agreement with experiment and is proposed as the structure of the P(b1) center.
RESUMO
A library of 80 analogues of the antibacterial compound mureidomycin was prepared using solid-phase chemistry techniques.
Assuntos
Antibacterianos/síntese química , Antibacterianos/farmacologia , Técnicas de Química Combinatória , Testes de Sensibilidade Microbiana , Nucleosídeos/síntese química , Nucleosídeos/química , Nucleosídeos/farmacologia , Relação Estrutura-AtividadeRESUMO
The vibrational properties of amorphous SiO2 were studied within first-principles density functional theory. The calculated spectrum is in good agreement with neutron data, showing, in particular, a double peak in the high-frequency region. This doublet results from different local modes of the tetrahedral subunits and cannot be ascribed to a longitudinal-optic-transverse-optic (LO-TO) effect. This solves a long-standing controversy about the origin of the doublet in neutron spectra. A LO-TO splitting is recovered only when the long-wavelength limit is probed, as in optical experiments. These findings should be a general feature of tetrahedral AX2 amorphous networks.
RESUMO
Imidazolidine-2,4-diones and 1,5-diphenyl tetramic acid derivatives were selected in order to evaluate some 5-membered heterocyclic ring compounds as potential templates for the synthesis of CCK receptor ligands. All the compounds were evaluated in vitro towards both CCK-B and CCK-A receptors.