High affinity and selectivity of [[(arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives for the 5-HT(1A) receptor. Synthesis and structure-affinity relationships.

In this work we report the affinity of new thienopyrimidinones for 5-HT(1A)Rs and the selectivity versus alpha(1)ARs. The 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]thio]-6-ethyl -thieno[2,3-d]pyrimidin-4(3H)-one 27 is the most potent and selective (Ki 0.19 nM, selectivity 115).

[[(Arylpiperazinyl)alkyl]thio]thieno[2,3-d]pyrimidinone derivatives as high-affinity, selective 5-HT1A receptor ligands.

A series of 2-[[(4-aryl-1-piperazinyl)alkyl]thio]thieno[2,3-d]pyrimidin-4 (1H)-one and 3-substituted 2-[[(4-aryl-1-piperazinyl)alky]thio]thieno[2,3-d]pyrimidin-4 (3H)-one derivatives was prepared and evaluated for in vitro 5-HT1A receptor affinity by radioligand binding assays; the selectivity for 5-HT1A receptors rather than alpha 1-adrenoceptors was also examined (ratio of the IC50 alpha 1 to IC50 5-HT1A). The binding tests gave indications about the best features of the [(arylpiperazinyl)alkyl]thio moiety and of the substituents on the thiophene and pyrimidinone rings for efficacious and selective 5-HT1A ligands. The most effective derivative for displacing [3H]-8-OH-DPAT from rat hippocampal membranes was the 3-amino-2-[[3-[4-(2-methoxyphenyl)-1-piperazinyl] propyl]thio]-5,6-dimethylthieno[2,3-d]pyrimidin-4(3H)-one (70) (IC50 = 0.

beta PP and Tau interaction. A possible link between amyloid and neurofibrillary tangles in Alzheimer's disease.

Extracellular deposition of amyloid fibrils and intraneuronal accumulation of paired helical filaments (PHFs) are the neuropathological hallmarks of Alzheimer's disease. The major constituent of amyloid fibrils is a 39- to 43-residue peptide (termed A beta), which is derived from a 695- to 770-amino-acid precursor protein (termed beta PP). The main component of PHFs identified so far is the microtubule-associated protein tau.

Manganese peroxidase from Phanerochaete chrysosporium. A homology-based molecular model.

A detailed three-dimensional model of manganese peroxidase was constructed using lignine peroxidase as the structural scaffold. This is the only protein in the peroxidase family except for cytochrome c peroxidase for which a resolved crystal structure is available. The model was built using the following procedure: (a) structurally preserved regions were derived from similar regions in the sequence alignment of the two proteins; (b) non-similar regions were modelled by searching a set of resolved protein structures for fragments which fitted in geometrically and choosing the best fitting fragment.

The chloroperoxidase-catalyzed oxidation of phenols. Mechanism, selectivity, and characterization of enzyme-substrate complexes.

The reactivity of a series of para-substituted phenolic compounds in the peroxidation catalyzed by chloroperoxidase was investigated, and the results were interpreted on the basis of the binding characteristics of the substrates to the active site of the enzyme. Marked selectivity effects are observed. These operate through charge, preventing phenolic compounds carrying amino groups on the substituent chain to act as substrates for the enzyme, and through size, excluding potential substrates containing bulky substituents to the phenol nucleus.

Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein.

Prion-related encephalopathies are characterized by cerebral accumulation of a post-translationally modified form of the cellular prion protein (PrPC), designated PrPSc. Evidence suggests that the conversion from PrPC to PrPSc involves changes in the secondary structure leading to an increase in beta-sheet content. We have previously shown that a synthetic peptide homologous to residues 106-126 of human PrP, belonging to a predicted alpha-helical domain, exhibits a beta-sheet conformation, forms amyloid-like fibrils, and is neurotoxic in vitro.

Migration of natural killer cells across endothelial cell monolayers.

Under certain conditions, NK cells accumulate rapidly at extrahematic sites. In an effort to define the mechanisms underlying recruitment of NK cells in tissues, we investigated their ability to migrate across endothelial cell (EC) monolayers. A considerable proportion of NK cells adhered to EC and about 30 to 40% of the adherent NK cells migrated across EC.

Molecular characteristics of a protease-resistant, amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein.

In the prion-related encephalopathies the prion protein is converted to an altered form, known as PrPSc, that is partially resistant to protease digestion. This abnormal isoform accumulates in the brain and its protease-resistant core aggregates extracellularly into amyloid fibrils. We have investigated the conformational properties, aggregation behaviour and sensitivity to protease digestion of a synthetic peptide homologous to residues 106-126 of human PrP, which was previously found to form amyloid-like fibrils in vitro and displayed neurotoxic activity toward primary cultures of rat hippocampal neurons.